JP2006528182A - Pharmaceutical preparations and treatment of digestive diseases caused by acids - Google Patents

Abstract

Provided herein is a powdered pharmaceutical formulation for suspension comprising at least one micronized proton pump inhibitor; at least one antacid; and at least one suspension. Also provided are methods of making and using pharmaceutical formulations comprising at least one proton pump inhibitor and at least one antacid.

Description

The present invention relates to pharmaceutical formulations comprising a proton pump inhibitor, at least one antacid, and at least one suspending agent. Also described are methods for producing such pharmaceutical formulations; methods for using the pharmaceutical formulations in the treatment of disease; and combinations of pharmaceutical formulations and other therapeutic agents. This application claims priority to US Provisional Application No. 60 / 488,324, filed July 18, 2003, the entire contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION Most acid labile pharmaceutical compounds must be protected from contact with acidic gastric secretions after ingestion in order to maintain pharmacological activity. To achieve this, enteric-coated compositions are designed to dissolve at a pH that ensures that the drug is released into the proximal region of the small intestine (the duodenum) and not in the acidic environment of the stomach Has been. However, due to the pH-dependent attributes of such enteric-coated compositions and the uncertainty of gastric retention time, what is the effect in vivo and both within and between subjects? However, it is a major weakness in using enteric coated systems for the purpose of allowing controlled release of drugs.

  Phillips et al. Also reported on pharmaceutical compositions without an enteric coating. Such a composition that allows immediate release of the pharmaceutically active ingredient into the stomach is a combination of one or more buffering agents with an acid labile pharmaceutical agent, such as a proton pump inhibitor. Requires administration. Buffers are believed to prevent substantial degradation of acid labile pharmaceutical agents in the acidic environment of the stomach by raising the pH. See, for example, US Pat. Nos. 5,840,737; 6,489,346; 6,645,988; and 6,699,885.

A series of acid labile pharmaceutical compounds administered as enteric coated dosage forms are proton pump inhibitors. Exemplary proton pump inhibitors include omeprazole (Prilosec®), lansoprazole (Prevacid®), esomeprazole (Nexium®), rabeprazole (Aciphex®), pantoprazole (Protonix®), pariprazole, tentaprazole, and leminoprazole. A series of drugs suppresses acid secretion from the digestive tract by specifically inhibiting the H ⁺ / K ⁺ -ATPase enzyme system (proton pump) on the secretory surface of the digestive wall cells. Most proton pump inhibitors are sensitive to acid degradation and are rapidly destroyed when the pH drops to acidic levels. Thus, if the enteric coating of such a formulated product is broken (eg, by doubling the compound into a liquid or chewing a capsule or tablet), or the buffer sufficiently increases the pH of the digestive system. If this cannot be neutralized, such drugs will be degraded by the gastrointestinal acid in the stomach.

  Omeprazole is a substituted bicyclic aryl-imidazole, 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole that inhibits gastrointestinal acid secretion Is an example of a proton pump inhibitor. US Pat. No. 4,786,505 by Lovgren et al. States that omeprazole pharmaceutical oral solid dosage forms must be protected from contact with acidic gastrointestinal fluids by an enteric coating in order to maintain their pharmaceutical activity Are described, and enteric-coated omeprazole preparations are described that include one or more subcoats between the central material and the enteric coating.

  Proton pump inhibitors typically include active duodenal ulcers, gastrointestinal ulcers, gastroesophageal reflux disease (GERD), severe erosive esophagitis, unresponsive symptomatic GERD, and Zollinger-Ellison syndrome It is prescribed for short-term treatment of pathological hypersecretion symptoms. The above conditions are generally found in healthy or critically ill patients of all ages and may be accompanied by significant upper gastrointestinal bleeding.

Omeprazole, lansoprazole, and other proton pump inhibitors reduce acid production in the digestive tract by inhibiting mural cell H ⁺ / K ⁺ -ATPase, the final common pathway of acid secretion from the digestive tract It is thought to let you. For example, Fellenius et al., Substituted Benzimidazoles Inhibit Gastrointestinal Acid Secretion by Blocking H ⁺ / K ⁺ -ATPase, Nature, 290: 159-161 (1981); Wallmark et al., The Relationship Between Gastrointestinal Acid Secretion and Gastrointestinal H ⁺ / K ⁺ -ATPase Activity, J. Biol. Chem., 260: 13681-13684 (1985); and Fryklund et al., Function and Structure of Parietal Cells After H ⁺ / K ⁺ -ATPase Blockade, Am. J Physiol., 254 (1988).

Proton pump inhibitors have the ability to act as weak bases that reach mural cells from the blood and disperse in secretory tubules. Here, the drug is captured by being protonated. Protonated compounds are then capable of covalently interacting with sulfhydryl groups at key sites in the extracellular (luminal) region of the transmembrane H ⁺ / K ⁺ -ATPase. There is a possibility to rearrange to form amides. See, for example, Hardman et al., Goodman &Gilman's The Pharmacological Basis of Therapeutics, 907 (9th edition, 1996). Thus, proton pump inhibitors are prodrugs that are effective only when activated. Features of the action of proton pump inhibitors are (a) selective distribution of H ⁺ / K ⁺ -ATPase; (b) the need for acidic conditions to catalyze the formation of reactive inhibitors; It also depends on (c) the protonated drug and cationic sulfonamide being trapped in acidic tubules and in the vicinity of the target enzyme. See, for example, Hardman et al.

  Accordingly, there is a need for a pharmaceutical formulation that can be administered in a stable and homogeneous suspension and in which the proton pump inhibitor is released into the stomach. With regard to patient compliance, there is also a need for improved formulations that mask the bitter taste of proton pump inhibitors and other excipients in order to provide palatable formulations.

SUMMARY OF THE INVENTION The present invention provides improved suspendability, bioavailability, chemical stability, physical stability, dissolution profile, disintegration time, safety, and other improved pharmacokinetic A pharmaceutical comprising at least one proton pump inhibitor, at least one antacid, and at least one suspending agent known to have pharmacodynamic chemical and / or physical properties Relates to the formulation. The pharmaceutical formulations of the invention are useful for administering suspensions to subjects.

  As used herein, a powdered pharmaceutical formulation for suspension (substantially homogeneous) comprising at least one micronized proton pump inhibitor; at least one antacid; at least one suspending agent. The suspension is obtained by mixing with water).

  As used herein, a powdered pharmaceutical formulation for suspension comprising at least one micronized proton pump inhibitor; at least one antacid; and a suspension (the suspension is a gum) (Mixing with water results in a first suspension that is substantially more uniform compared to a second suspension comprising a proton pump inhibitor, an antacid, a flavoring agent, and a suspending agent ( Suspensions are not gums))).

  Provided herein is a pharmaceutical formulation comprising (a) at least one acid labile micronized proton pump inhibitor; and (b) at least one antacid. (A) coating at least a portion of at least one antacid with at least a portion of a micronized proton pump inhibitor to obtain a first blend; and (b) a first blend. Made by a method comprising dry blending with at least one other excipient).

As used herein, conditions or disorders such as acid-induced gastrointestinal diseases are administered by administering a pharmaceutical formulation of the invention when treatment with an inhibitor of H ⁺ / K ⁺ -ATPase is indicated. A method of treatment is also provided.

DETAILED DESCRIPTION OF THE INVENTION The present invention is for administration of a suspension comprising at least one proton pump inhibitor, at least one antacid, at least one suspension; and at least one flavor. A pharmaceutical formulation is provided.

The present invention also treats conditions or disorders directed to treatment with inhibitors of H ⁺ / K ⁺ -ATPase, such as acid-induced gastrointestinal diseases, by administering the pharmaceutical formulations of the present invention Also related to the method.

  While this invention may be embodied in a wide variety of forms, this disclosure is intended to be illustrative only of the principles of the invention and is not intended to limit the invention to the described embodiments. Under specific conditions, some specific aspects are described.

  In order to facilitate an understanding of the present invention and preferred embodiments of the present invention, the meanings of terms and expressions used in this specification are the general usage of various terms and expressions, and the following glossary or the following description. It will become apparent from the context of this specification in view of the clear definitions of other terms and expressions provided in.

Glossary As used herein, the expressions “comprising”, “including”, and “such as” are used in a completely non-limiting sense. The

  The expression “about” is used interchangeably with the expression “approximately”. Although illustrative, the use of the expression “about” means a value that deviates slightly from the quoted value (eg, in the range of ± 0.1% to 10%) that is effective and safe. Accordingly, such doses are included within the scope of using the expressions “about” and “approximately”.

  The expression “acid-labile pharmaceutical agent” means any pharmacologically active agent that undergoes acid-catalyzed degradation.

  “Aftertaste” is one measure of any sensation that remains after swallowing. Aftertaste is, for example, 30 seconds after swallowing, 1 minute after swallowing, 2 minutes after swallowing, 3 minutes after swallowing, 4 minutes after swallowing, 5 minutes after swallowing It can be measured at a time such as from.

  The expression “amplitude” is the initial overall sense of flavor balance and integrity. The amplitude scale is 0 for “none”, 1 for “low”, 2 for “medium”, and 3 for “high”.

  An “anti-adhesive”, “glue enhancer”, or “anti-adhesive” improves the flowability of a material by preventing the ingredients of the formulation from aggregating or adhering. Such compounds include, for example, colloidal silicon dioxide such as Cab-o-sil®; tribasic calcium phosphate, talc, corn starch, DL-leucine, sodium lauryl sulfate, magnesium stearate, calcium stearate, sodium stearate , Kaolin, and finely divided amorphous silicon dioxide (Syloid®).

  “Antifoaming agents” suppress foaming during processing that can lead to agglomeration of the dispersion in the water, create bubbles in the final film, or generally cause the processing to fail. Exemplary antifoaming agents include silicon emulsion and sorbitan sesquioleate.

  “Antioxidants” include, for example, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium ascorbate, and tocopherol.

  A “binder” imparts tackiness. Binders include, for example, alginic acid and its salts; carboxymethylcellulose, methylcellulose (eg Methocel®), hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (eg Klucel®), ethylcellulose (eg Ethocel®). )), And cellulose derivatives such as microcrystalline cellulose (eg Avicel®); microcrystalline dextrose; amylose; magnesium aluminum silicate; polysaccharide acid; bentonite; gelatin; polyvinylpyrrolidone / vinyl acetate copolymer; Povidone; povidone; starch; pregelatinized starch; tragacanth, dextrin, sucrose (eg Dipac®), glucose, dextrose, molasses, Sugars such as mannitol, sorbitol, xylitol (eg Xylitab®) and lactose; natural gums or acacia, tragacanth, gati gum, isapol husk adhesives, polyvinylpyrrolidone (eg Polyvidone® CL, Kollidon® (Trademark) CL, Polyplasdone (registered trademark) XL-10) and other synthetic rubbers, larch arabogalactan, Veegum (registered trademark), polyethylene glycol, wax, sodium alginate and the like.

  The expression “bioavailability” means the extent to which an active moiety, such as a drug, prodrug, or metabolite is absorbed into the systemic circulation and becomes available at the site of drug action in the body. Therefore, the bioavailability of the proton pump inhibitor administered intravenously is 100%. The expression “oral bioavailability” means the scale at which a proton pump inhibitor is absorbed into the systemic circulation and becomes available at the site of drug action in the body when the pharmaceutical formulation is taken orally.

The expression “bioequivalence” or “bioequivalent” means that the area under the serum concentration time curve (AUC) and peak serum concentration (C _max ) are within 80% and 125%, respectively. Means that.

  The “carrier material” should include any excipient commonly used in the pharmaceutical field and should be selected based on compatibility with the proton pump inhibitor and the release profile characteristics of the desired dosage form. . Exemplary carrier materials include, for example, binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like. “Pharmaceutically compatible carrier materials” include, for example, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, phosphorus Examples include tricalcium acid, dipotassium phosphate, sodium stearyl lactate, carrageenan, monoglyceride, diglyceride and pregelatinized starch. For example, Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa .: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman , HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, l999).

  “Character notes” include, for example, aromatics, basic tastes, and feeling factors. The strength of the characteristic index is represented by a scale of 0 for “none”, 1 for “slight”, 2 for “medium”, or 3 for “strong”.

  A “derivative” is a compound made from another compound having a similar structure by replacing an atom, molecule, or functional group with another suitable atom, molecule, or functional group. For example, one or more hydrogen atoms of a compound may be one or more alkyl groups, acyl groups, amino groups, hydroxyl groups, halo groups, haloalkyl groups, aryl groups, heteroaryl groups, cycloalkyl groups, heterocycloalkyl Group or a heteroalkyl group can be substituted to obtain a derivative of the target compound.

  “Diffusion enhancers” and “dispersants” include materials that control the diffusion of an aqueous fluid through a coating. Exemplary diffusion promoters / dispersants include, for example, hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, and the like. In the present invention, a combination of one or more erosion promoters and one or more diffusion promoters can also be used.

  “Diluents” increase the bulk of the composition and promote compression. Such compounds include, for example, lactose; starch; mannitol; sorbitol; dextrose; microcrystalline cellulose such as Avicel®; calcium hydrogen phosphate; dicalcium phosphate dihydrate; tricalcium phosphate; calcium phosphate; Anhydrous lactose; spray-dried lactose; pregelatinized starch; compressible sugar such as Di-Pac® (Amstar); mannitol; hydroxypropylmethylcellulose; sucrose-based diluent; powdered sugar; Calcium hydrogen monohydrate; Calcium sulfate dihydrate; Calcium lactate trihydrate; Dextrate; Hydrolyzed cereal solid; Amylose; Powdered cellulose; Calcium carbonate; Glycine; Kaolin; Sodium chloride; inositol; bentona Theft, and the like.

  The expression “disintegrates” includes both dissolution and dispersion of the dosage form upon contact with gastrointestinal fluid.

  A “disintegrant” promotes the degradation or disintegration of a substance. Examples of disintegrants include starches such as natural starches such as corn starch and potato starch, pregelatinized starches such as National 1551 and Amijel®, or glycolic acids such as Promogel® and Explotab® Sodium starch; wood product, methylcrystalline cellulose, eg Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® ) Cellulose, such as P100, Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, methylcellulose, croscarmellose or cross-linked sodium carboxymethylcellulose (Ac-Di-Sol) (Registered trademark)), crosslinked carboxymethylcellulose, or crosslinked croscarmellose Any cross-linked cellulose; cross-linked starch such as sodium starch glycolate; cross-linked polymer such as crospovidone; cross-linked polyvinyl pyrrolidone; alginates such as alginic acid or a salt of alginic acid such as sodium alginate; Veegum® HV (magnesium aluminum silicate) Clay such as agar, guar, locust bean, Karaya, pectin, or tragacanth; sodium glycolate starch; bentonite; natural sponge; surfactant; resin such as cation exchange resin; citrus pulp; Sodium lauryl sulfate; sodium lauryl sulfate in combination starch and the like.

  The phrase “drug absorption” or “absorption” refers to the process of moving from the site of drug administration into the systemic circulation (eg, into a subject's bloodstream).

  An “enteric coating” is a substance that remains substantially intact in the stomach but dissolves and releases the drug when it reaches the small intestine. In general, enteric coatings prevent release in the low pH environment of the stomach, but ionize at slightly higher pH (typically pH 4 or 5) to dissolve well in the small intestine and dissolve the active agent in the small intestine. A polymeric material that gradually releases.

  The expression “enteric proton pump inhibitor” means that part or most of the proton pump inhibitor is enterically coated and at least part of the drug is proximal to the small intestine rather than to the acidic environment of the stomach. It means that it is reliably released into the area (duodenum).

  An “erosion facilitator” includes materials that control the erosion of certain materials in the gastrointestinal fluid. Erosion promoters are generally known to those skilled in the art. Exemplary erosion promoters include, for example, hydrophilic polymers, electrolytes, proteins, peptides, and amino acids.

  “Fillers” include lactose, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose; dextrate; dextran, starch, pregelatinized starch, sucrose, xylitol, lactitol, There are compounds such as mannitol, sorbitol, sodium chloride and polyethylene glycol.

  “Flavoring agents” or “sweetening agents” useful in the pharmaceutical composition of the present invention include, for example, acacia syrup, acesulfame K, aritem, anise, apple, aspartame, banana, bavaroa cream, berry, black currant, butterscotch, quencher Calcium acid, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherries, cool citrus, cyclamate, cyclamate, dextrose, eucalyptus, eugenol, Fructose, fruit punch, ginger, glycyrrhizic acid, licorice (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammoni glycyrrhizinate Umm (MagnaSweet (registered trademark)), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidin DC, neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet (registered trademark) powder, Raspberry, root beer, rum, saccharin, safrole, sorbitol, mint, mint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, saccharin sodium, saccharin, aspartame, acesulfame potassium, mannitol, tallin, sylitol, sucralose , Sorbitol, Swiss cream, tagatose, tangerine, thaumatin, Tutti Frutti, vanilla, walnut, watermelon, wild cherries, winter green oil, ki Ritolol, or any combination of these flavor ingredients, such as anise-menthol, cherry-anis, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange -Cream, vanilla-mint, and mixtures thereof.

  “Gastrointestinal fluid” is the fluid of the subject's gastric secretions, or the saliva of the subject, or the equivalent after oral administration of the composition of the present invention. “Equivalents of gastric secretions” include, for example, in vitro fluids having similar contents and / or pH as gastric secretions, such as 1% sodium dodecyl sulfate solution and 0.1 N HCl aqueous solution.

  The expression “half-life” means the time required for a plasma drug concentration or amount in the body to decrease by 50% from its maximum concentration.

  A “lubricant” is a compound that prevents, reduces or inhibits material adhesion or friction. Exemplary lubricants include, for example, stearic acid; calcium hydroxide; talc; sodium stearyl fumarate; hydrocarbons such as mineral oil or hydrogenated soybean oil (Sterotex®); higher fatty acids; and This alkali metal, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearate, glycerol, talc, wax, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol Salts and alkaline earth metal salts, or methoxypolyethylene glycol such as Carbowax ™, sodium oleate, glyceryl behenate, polyethylene glycol, magnesium lauryl sulfate or sodium lauryl sulfate, Syloid ™, Colloidal silica such as Carb-O-Sil (registered trademark), starch such as corn starch, silicone oil, surfactant and the like.

  “Measurable serum concentration” or “Measurable plasma concentration” is typically mg / ml of serum, 1 ml, 1 dl, or 1 l of therapeutic agent absorbed into the bloodstream after administration. Mean serum concentration or plasma concentration measured as a therapeutic agent, .mu.g, or ng. One skilled in the art would be able to measure serum or plasma concentrations of proton pump inhibitors or motor function improvers. For example, see Gonzalez H. et al., J. Chromatogr. B. Analyt. Technol. Biomed. Life Sci., Vol. 780, pp459-65, (Nov. 25, 2002).

  A “parietal cell activator” or “activator” stimulates mural cells to increase the pharmacological activity of the proton pump inhibitor. Wall cell activators include, for example, chocolate; alkaline substances such as sodium bicarbonate; calcium such as calcium carbonate, calcium gluconate, calcium hydroxide, calcium acetate, and calcium glycerophosphate; peppermint oil; mint oil; coffee; Cola (including decaffeinated); caffeine; theophylline; theobromine; amino acids (especially aromatic amino acids such as phenylalanine and tryptophan); and combinations thereof.

  The expression “pharmacodynamic factor” means a factor that determines the observed biological response to the concentration of drug at the site of action.

  The expression “pharmacokinetic factor” means a factor that determines the arrival and maintenance of an appropriate concentration of drug at the site of action.

The expression “plasma concentration” means the concentration of a substance in the plasma or serum of a subject. It is understood that the plasma concentration of a therapeutic agent can vary from subject to subject by several fold due to variations in the metabolism of the therapeutic agent. In one aspect of the invention, the plasma concentration of the proton pump inhibitor and / or motor function improving agent may vary between subjects. Similarly, values such as maximum plasma concentration (C _max ), time to reach maximum serum concentration (T _max ), or area under the serum concentration time curve (AUC) may vary from subject to subject. Because of such variations, the amount necessary to constitute a “therapeutically effective amount” of a proton pump inhibitor, motor function improving agent, or other therapeutic agent may vary from subject to subject. Where the mean plasma concentration of the subject population is shown, it is understood that such mean value may include significant variation.

  A “plasticizer” is a compound used to soften a microencapsulating material or film coating so that it does not become brittle. Suitable plasticizers include, for example, polyethylene glycols such as PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, and triacetin.

  The terms “prevent” or “prevent” when used in reference to a gastric acid-related disease indicate that no gastrointestinal disorder or onset of disease has been observed if nothing has occurred, or If an onset of a gastrointestinal disorder or disease is already seen, this means that there is no further onset of gastrointestinal disorder or disease. The ability to prevent some or all of the symptoms associated with a digestive disorder or disease is also considered.

  The expression “prodrug” means a drug or compound whose pharmacological action results from conversion by metabolic processes in the body. Prodrugs are generally drug precursors that, after administration to a subject and subsequent absorption, undergo a number of processes, such as conversion by metabolic pathways, to convert them into active or highly active molecular species. Some prodrugs have functional groups on the prodrug that weaken its activity and / or confer solubility or some other property to the same drug. Active agents are generated when functional groups are cleaved and / or modified from prodrugs. Prodrugs can be designed as reversible drug derivatives for use as modifiers to enhance drug transport to site-specific tissues. To date, prodrug designs have enhanced the effective solubility of therapeutic compounds in water to target areas where water is the primary solvent. For example, Fedorak et al., Am. J. Physiol., 269: G210-218 (1995); McLoed et al., Gastroenterol, 106: 405-413 (1994), Hochhaus et al., Biomed. Chrom. ., 6: 283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988) Sinkula et al., J. Pharm. Sci., 64: 181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series; and Edward See B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987.

  The expression “proton pump inhibitor product” means a commercial product. Proton pump inhibitor products include, for example, Priolosec (R), Nexium (R), Prevacid (R), Protonic (R), and Aciphex (R).

The expression “serum concentration” means the concentration of a substance, such as a therapeutic agent, contained in a subject's plasma or serum. It is understood that the serum concentration of a therapeutic agent may vary several times between subjects due to metabolic variations in the therapeutic agent. In one aspect of the invention, the serum concentration of the proton pump inhibitor and / or motor function improving agent may vary between subjects. Similarly, values such as maximum serum concentration (C _max ), time to maximum serum concentration (T _max ), or total area under the serum concentration time curve (AUC) may vary from subject to subject . Because of such variations, the amount required to make up a “therapeutically effective amount” of a proton pump inhibitor, motor function improving agent, or other therapeutic agent may vary from subject to subject. It is understood that such mean values may include significant variation where mean serum concentrations for the subject population are shown.

  “Solubilizers” include compounds such as citric acid, succinic acid, fumaric acid, malic acid, tartaric acid, maleic acid, glutaric acid, sodium bicarbonate, sodium carbonate and the like.

  “Stabilizer” includes any antioxidant, buffer, compound such as acid, and the like.

  “Suspending agents” or “thickening agents” include polyvinylpyrrolidone (eg, polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30); polyethylene glycol (the molecular weight of polyethylene glycol is, for example, about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400); sodium carboxymethylcellulose; methylcellulose; hydroxy-propylmethylcellulose; polysorbate-80; hydroxyethylcellulose; sodium alginate; gum (eg, tragacanth gum or acacia gum) Guar gum; xanthan (including xanthan gum); sugars; cellulosic materials (eg sodium carboxymethylcellulose, methylcellulose, sodium carboxymethyl) Cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose); polysorbate-80; sodium alginate; polyethoxylated sorbitan monolaurate; polyethoxylated sorbitan monolaurate; include compounds such as povidone.

  “Surfactants” include sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, poloxamer, bile salt, glyceryl monostearate, a copolymer of ethylene oxide and propylene oxide (eg Pluronic) (Registered trademark) (BASF)) and the like.

  A “therapeutically effective amount” or “effective amount” is the amount of a pharmaceutical agent to achieve a pharmacological effect. The expression “therapeutically effective amount” includes, for example, a prophylactically effective amount. An “effective amount” of a proton pump inhibitor is an amount effective to achieve the desired pharmacological effect or therapeutic improvement without causing undue adverse side effects. For example, an effective amount of a proton pump inhibitor reduces acid secretion or raises the pH of gastrointestinal fluid or reduces gastrointestinal bleeding or reduces the need for blood transfusion or improves survival Or the amount of proton pump inhibitor that results in a faster recovery from gastric acid related diseases. An effective amount of the pharmaceutical agent is selected by one skilled in the art depending on the particular patient and the level of the disease. “Effective amount” or “therapeutically effective amount” refers to metabolic variations in therapeutic agents such as proton pump inhibitors and / or motor function improvers, subject age, weight, general conditions, condition to be treated, treatment It is understood that it may vary from subject to subject due to the severity of the subject condition and the judgment of the treating physician.

  “Total fragrance intensity” is a rapidly appearing overall impression of fragrance intensity, including both fragrance and sensation felt by the nose.

  “Total flavor intensity” is a rapidly appearing overall impression of flavor intensity, including aroma, basic taste, and sensations felt in the mouth.

  As used in the context of gastric acid related diseases, the phrase “treating” or “treatment” refers to a disorder or a disorder in a subject who may be suffering from a disorder or disease but has not yet been diagnosed as a disorder or disease. Preventing the onset of a disease; suppressing the progression of the disease or disorder (eg, stopping the onset of the disorder or disease, alleviating the disorder or disease, bringing about the recovery of the disorder or disease, Or any treatment of a disorder or disease associated with a digestive disorder, such as prevention of a disorder or disease, such as relieving a condition resulting from the disorder or stopping symptoms of the disease or disorder. Accordingly, the expression “treating” as used herein is used interchangeably with the expression “preventing”.

  “Wetting agents” include oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate And compounds such as sodium lauryl sulfate.

Proton Pump Inhibitors The expressions `` proton pump inhibitor '', `` PPI '', and `` agent that inhibits proton pump '' refer to acids that have pharmacological activity as inhibitors of H ⁺ / K ⁺ -ATPase. May be used interchangeably in expressing any unstable pharmaceutical agent. Proton pump inhibitors are therapeutically the free base, salt, ester, hydrate, amide, enantiomer, isomer, tautomer, prodrug, or any other pharmacologically appropriate derivative. If active, if desired, such as free base, free acid, salt, ester, hydrate, anhydride, amide, enantiomer, isomer, tautomer, prodrug, polymorph, derivative, etc. May take shape.

  The proton pump inhibitor may be a substituted bicyclic aryl-imidazole (the aryl group may be, for example, a pyridine group, a phenyl group, or a pyrimidine group, and is bonded to the 4th and 5th positions of the imidazole ring). ) Proton pump inhibitors including substituted bicyclic arylimidazoles include, for example, omeprazole, hydroxyomeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole, dontoprazole, habeprazole, periprazole, tenatoprazole, lansoprazole , Parisprazole, leminoprazole, or their free base, free acid, salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, prodrug, or derivative . See, for example, The Merck Index, Merck & Co. Rahway, N.J. (2001).

  Other proton pump inhibitors include, for example, soraprazan (Altana); ilaprazole (US Pat. No. 5,703,097) (Il-Yang); AZD-0865 (AstraZeneca): YH-1885 (PCT Publication WO 96/05177 ); (SB-641257) (2-pyrimidineamine, 4- (3,4-dihydro-1-methyl-2 (1H) -isoquinolinyl) -N (4-fluorophenyl) -5,6-dimethyl-, mono Hydrochloric acid) (YuHan); BY-112 (Altana); SP1-447 (imidazo (1,2-a) thieno (3,2-c) pyridin-3-amine, 5-methyl-2- (2-methyl- 3-thienyl); 3-hydroxymethyl-2-methyl-9-phenyl-7H-8,9-dihydro-pyrano (2,3-c) -imidazo (1,2-a) pyridine (PCT Publication) WO 95/27714) (AstraZeneca); Pharmaprojects No. 4950 (3-hydroxymethyl-2methyl-9phenyl-7H-8,9-dihydro-pyrano (2,3-c) -imidazo (1,2-a) Pyridine) (AstraZeneca, discontinued), WO 95/27714; Pharmapro jects No. 4891 (EP 700899) (Aventis); Pharmaprojects No. 4697 (PCT Publication WO 95/32959) (AstraZeneca); H-335 / 25 (AstraZeneca); T-330 (Saitama 335) (Pharmacological Research Lab); Pharmaprojects No. 3177 (Roche); BY-574 (Altana); Pharmaprojects No. 2870 (Pfizer); AU-1421 (EP 264883) (Merck); AU-2064 (Merck); AY-28200 (Wyeth); Pharmaprojects No .2126 (Aventis); WY-26769 (Wyeth); Pumaprazole (PCT Publication WO 96/05199) (Altana); YH-1238 (YuHan); Pharmaprojects No. 5648 (PCT Publication WO 97/32854) (Dainippon); BY -686 (Altana); YM-020 (Yamanouchi); GYKI-34655 (Ivax); FPL-65372 (Aventis); Pharmaprojects No. 3264 (EP 509974) (AstraZeneca); Nepaprazole (Toa Eiyo); HN-11203 (Nycomed) Pharma); OPC-22575; pumilacidin A (BMS); saviprazole (EP 234485) (Aventis); SK and F-95601 (GSK, discontinued); Phar maprojects No. 2522 (EP 204215) (Pfizer); S-3337 (Aventis); RS-13232A (Roche); AU 1363 (Merck); SK and F-96067 (EP 259174) (Altana); SUN 8176 (Daiichi Phama) Ro-18-5362 (Roche); Ufiprazole (EP 74341) (AstraZeneca); and Bay-p-1455 (Bayer); or the free bases, free acids, salts, water of these compounds Examples include Japanese, ester, amide, enantiomer, isomer, tautomer, polymorph, prodrug, or derivative.

  Still other proton pump inhibitors include US Pat. Nos. 4,628,098; 4,689,333; 4,786,505; 4,853,230; 4,965,269; 5,021,433; 5,026,560; 5,045,321; 5,093,132; No. 5,433,959; No. 5,576,025; No. 5,639,478; No. 5,703,110; No. 5,705,517; No. 5,708,017; No. 5,731,006; No. 5,824,339; No. 5,855,914; No. 5,879,708; No. 5,948,773; 6,123,962; 6,187,340; 6,296,875; 6,319,904; 6,328,994; 4,255,431; 4,255,431; 4,508,905; 4,636,499; 4,738,974; 5,690,960; 5,714,504; 5,338,817 No. 6,093,734; No. 6,013,281; No. 6,136,344; No. 6,183,776; No. 6,328,994; No. 6,479,075; No. 6,559,167

  Other substituted bicyclic aryl-imidazole compounds and their salts, hydrates, esters, amides, enantiomers, isomers, tautomers, polymorphs, prodrugs, and derivatives are It can be prepared by standard procedures known to those skilled in the art. For example, March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed. (New York: Wiley-Interscience, 1992), Leonard et al., Advanced Practical Organic Chemistry, (1992); Howarth et al; Core See Organic Chemistry (1998); and Weisermel et al., Industrial Organic Chemistry (2002).

  “Pharmaceutically acceptable salts” or “salts” include, for example, formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid , Fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, mesylic acid, stearic acid, salicylic acid, paraoxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (embonic), methanesulfonic acid, ethanesulfonic acid, Salts of proton pump inhibitors prepared from benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, alginic acid, b-hydroxybutyric acid, galactaric acid, and galacturonic acid Including.

  Acid addition salts are prepared from the free base in a conventional manner involving the reaction of the free base with the appropriate acid. Suitable acids for preparing acid addition salts include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid. Organic acids such as acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid .

  The acid addition salt is reconverted to the free base by treatment with a suitable base. The acid addition salt of the proton pump inhibitor may be a halide salt prepared using hydrochloric acid or hydrobromic acid. Examples of basic salts include alkali metal salts (for example, sodium salts and copper salts).

  Salts of proton pump inhibitors include, for example, sodium salts such as esomeprazole sodium, omeprazole sodium, rabeprazole sodium, pantoprazole sodium; or esomeprazole magnesium or omeprazole described in US Pat. No. 5,900,424. Magnesium salts such as magnesium; or calcium salts; or potassium salts such as esomeprazole potassium salts described in US Patent Application No. 02/0198239 and US Pat. No. 6,511,996. Other salts of esomeprazole are described in US Pat. No. 4,738,974 and US Pat. No. 6,369,085. Pantoprazole and lansoprazole salts are described in US Pat. Nos. 4,758,579 and 4,628,098, respectively.

Preparation of the ester involves the addition of functional groups to hydroxyl and / or carboxyl groups present in the molecular structure of the drug. For example, the ester may be an acyl-substituted derivative of a free alcohol group (for example, a moiety derived from a carboxylic acid represented by the chemical formula RCOOR ₁ (R ₁ is a lower alkyl group)). The ester can be reconverted to the free acid by conventional procedures such as hydrogenolysis and hydrolysis if desired.

  “Amides” can be prepared by techniques known to those skilled in the art or as described in the relevant literature. For example, amides can be prepared from esters using appropriate amine reactants, as well as from anhydrides or acid chlorides by reaction with amine groups such as ammonia and lower alkyl amines.

  “Tautomers” of substituted bicyclic aryl-imidazoles include, for example, US Pat. Nos. 6,262,085; 6,262,086; 6,268,385; 6,312,723; 6,316,020; 6,326,384; 6,369,087; There are tautomers of omeprazole as described in US 6,444,689, as well as in US Patent Application No. 02/10156103.

  An exemplary “isomer” of a substituted bicyclic aryl-imidazole is an isomer of omeprazole. See, for example, Oishi et al., Acta Cryst. (1989), C45, 1921-1923, US Pat. No. 6,150,380; US Patent Application No. 02/0156284; and PCT Publication No. WO 02/085889. I want.

  Exemplary “polymorphs” include, for example, WO 92/08716; and US Pat. Nos. 4,045,563; 4,182,766; 4,508,905; 4,628,098; 4,636,499; 4,689,333; 4,758,579 4,783,974; 4,786,505; 4,808,596; 4,853,230; 5,026,560; 5,013,743; 5,035,899; 5,045,321; 5,045,552; 5,093,132; 5,093,433; 5,464,632; 5,536,735; 5,576,025; 5,599,794; 5,629,305; 5,639,478; 5,690,960; 5,703,110; 5,705,517; 5,714,504; 5,731,006; 5,879,708; 5,948,773; No. 5,997,903; No. 6,017,560; No. 6,123,962; No. 6,147,103; No. 6,150,380; No. 6,166,213; No. 6,191,148; No. 5,187,340; No. 6,268,385; 6,296,875; 6,316,020; 6,328,994; 6,326,384; 6,369,085; 6,369,087 ; And the like as described in and No. 6,462,0577; No. 6,380,234; No. 6,428,810; No. 6,444,689.

  A “derivative” is a compound made from another compound having a similar structure by substitution of an atom, molecule, or functional group for another suitable atom, molecule, or functional group. For example, one or more hydrogen atoms of a compound may be substituted with one or more alkyl groups, acyl groups, amino groups, hydroxyl groups, halo groups, haloalkyl groups, aryl groups, heteroaryl groups, cycloalkyl groups, heterocycloalkyl groups. Alternatively, a derivative of the target compound can be obtained by substituting with a heteroalkyl group.

  The expression “prodrug” means a drug or compound whose pharmacological action is manifested by conversion by metabolic processes in the body. Prodrugs are generally drug precursors that are converted to an active or more active molecular species through several steps, such as administration to a subject and subsequent absorption followed by conversion by metabolic pathways. . Some prodrugs have functional groups on the prodrug to weaken the activity of the prodrug and / or to provide a drug with some solubility or some other property. Functional groups are cleaved and / or modified from prodrugs to yield active agents.

  Prodrugs can be designed as reversible drug derivatives for use as modifiers to enhance drug transport to site-specific tissues. To date, prodrug designs target the region where water is the primary solvent, thus increasing the effective water solubility of therapeutic compounds. For example, Fedorak, et al., Am. J. Physiol, 269: G210-218 (1995); McLoed, et al., Gastroenterol., 106: 405-413 (1994); Hochhaus, et al., Biomed. Chrom., 6: 283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64: 181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series And Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987.

Micronized proton pump inhibitor The particle size of the proton pump inhibitor can affect the solid dosage form in a number of ways. Since particle size reduction increases surface area (S), particle size reduction leads to an increase in dissociation rate (dM / dt), as expected from the following Noyes-Whitney equation:
dM / dt = dS / h (C _s -C)
M = mass of dissolved drug; t = time; D = diffusion coefficient of drug; S = effective surface area of drug particles; H = static layer thickness; C _s = solution concentration at saturation; and C = solution at time t concentration.

  Because omeprazole, as well as other proton pump inhibitors, are poorly water soluble, in various aspects of the invention, micronized omeprazole is used to formulate drug products in order to facilitate rapid dissolution of the drug product. In general, if the size of the particles is the same, increasing the surface area will increase the rate of bioabsorption of drugs that are significantly less water soluble. The small size of the particles also acts to maintain good suspendability. This is because smaller particles are less likely to “settling”. Therefore, there is also a relationship between particle size and suspendability.

  A pharmaceutical formulation comprising micronized omeprazole is described. In some embodiments, the average particle size of at least about 90% of micronized omeprazole is less than about 100 μm, or less than about 80 μm, less than about 60 μm, or less than about 40 μm, or less than about 35 μm, or about 30 μm. Less than, or less than about 25 μm, or less than about 20 μm, or less than about 15 μm, or less than about 10 μm, or less than about 5 μm. In other embodiments, the average particle size of at least 80% of micronized omeprazole is less than about 100 μm, or less than about 80 μm, less than about 60 μm, or less than about 40 μm, or less than about 35 μm, or less than about 30 μm, Or less than about 25 μm, or less than about 20 μm, or less than about 15 μm, or less than about 10 μm, or less than about 5 μm. In yet other embodiments, the average particle size of at least 70% of micronized omeprazole is less than about 100 μm, or less than about 80 μm, less than about 60 μm, or less than about 40 μm, or less than about 35 μm, or less than about 30 μm Or less than about 25 μm, or less than about 20 μm, or less than about 15 μm, or less than about 10 μm, or less than about 5 μm.

  The size of micronized omeprazole is within about 1 hour of dissolution test, or within about 50 minutes, or within about 40 minutes, or within about 30 minutes, or within about 20 minutes, or about 10 minutes Also described are pharmaceutical formulations that allow more than 75% of the proton pump inhibitor released within or within about 5 minutes. In some embodiments of the invention, the size of micronized omeprazole is such that 90% or more of the proton pump inhibitor is within about 1 hour of dissolution test, within about 50 minutes, or within about 40 minutes. Or a size that allows release within about 30 minutes, or within about 20 minutes, or within about 10 minutes, or within about 5 minutes.

Antacids The pharmaceutical composition of the present invention comprises one or more antacids. A series of antacids useful in the present invention include, for example, antacids having pharmacological activity as weak or strong bases. In one embodiment, the antacid is due to the acid of the proton pump inhibitor by gastrointestinal fluid when formulated with or transported with the proton pump inhibitor (eg, before, during, and / or thereafter). Degradation, for example, functions to substantially prevent or inhibit the bioavailability of the proton pump inhibitor to be administered for a period sufficient to preserve.

  In one aspect of the invention, the antacid is a Group IA metal salt, such as a Group IA metal salt bicarbonate, a Group IA metal carbonate, an alkaline earth metal antacid, an aluminum antacid , Calcium antacid, or magnesium antacid.

  Other antacids suitable for the present invention include, for example, alkali metal (sodium and potassium) or alkaline earth metal (calcium and magnesium) carbonates, phosphates, bicarbonates, citrates, boric acid. Salts, acetates, phthalates, tartrate, succinates, etc. (such as sodium or potassium phosphates, citrates, borates, acetates, bicarbonates and carbonates).

  In the present specification, amino acid, acid salt of amino acid, alkali salt of amino acid, aluminum hydroxide, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitate, aluminum hydroxide, aluminum hydroxide / magnesium hydroxide coprecipitate, Aluminum hydroxide / sodium bicarbonate coprecipitate, aluminum glycinate, calcium acetate, calcium bicarbonate, calcium borate, calcium carbonate, calcium citrate, calcium gluconate, calcium glycerophosphate, calcium hydroxide, calcium lactate, calcium phthalate , Calcium phosphate, calcium succinate, calcium tartrate, disodium phosphate, dipotassium hydrogen phosphate, dipotassium phosphate, disodium hydrogen phosphate, disodium succinate, dry aluminum hydroxide gel , L-Arginine, Magnesium acetate, Magnesium aluminate, Magnesium borate, Magnesium bicarbonate, Magnesium carbonate, Magnesium citrate, Magnesium gluconate, Magnesium hydroxide, Magnesium lactate, Magnesium aluminate metasilicate, Magnesium oxide, Magnesium phthalate , Magnesium phosphate, magnesium silicate, magnesium succinate, magnesium tartrate, potassium acetate, potassium carbonate, potassium bicarbonate, potassium borate, potassium citrate, potassium metaphosphate, potassium phthalate, potassium phosphate, potassium polyphosphate, Potassium pyrophosphate, potassium succinate, potassium tartrate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate, gluconic acid Thorium, sodium hydrogen phosphate, sodium hydroxide, sodium lactate, sodium phthalate, sodium phosphate, sodium polyphosphate, sodium pyrophosphate, sodium sesquicarbonate, sodium succinate, sodium tartrate, sodium tripolyphosphate, synthetic hydrotalcite, Provided is a pharmaceutical formulation comprising at least one antacid selected from tetrapotassium pyrophosphate, tetrasodium pyrophosphate, dipotassium phosphate, trisodium phosphate, and trometamol. Partly based on the list described in The Merck Index, Merck & Co. Rahway, N.J. (2001).

  In addition, since proteins or protein hydrolysates may react rapidly with acids, they may also act as antacids in the present invention. Also, combinations of the above antacids can be used in the pharmaceutical formulations described herein.

  Antacids useful in the present invention include antacids or combinations of antacids that interact with hydrochloric acid (or other acids depending on the target environment) more quickly than when the proton pump inhibitor interacts with hydrochloric acid. There are also. When such an antacid is present in a liquid phase such as water, it exhibits a large pH compared to the proton pump inhibitor pKa and persists at the same pH.

  In the present specification, at least one antacid is selected from the group consisting of sodium bicarbonate, sodium carbonate, calcium carbonate, magnesium oxide, magnesium hydroxide, magnesium carbonate, aluminum hydroxide, and mixtures thereof. Provide a pharmaceutical formulation. In one embodiment, the antacid is sodium bicarbonate and is present at a concentration of about 0.1 mEq / mg proton pump inhibitor to about 5 mEq / mg proton pump inhibitor. In another embodiment, the antacid is a mixture of sodium bicarbonate and magnesium hydroxide (sodium bicarbonate and magnesium hydroxide are each about 0.1 mEq / mg proton pump inhibitor to about 5 mEq / mg proton pump inhibitor) Present in the concentration of the agent). In yet another aspect, the antacid is a mixture of sodium bicarbonate, calcium carbonate, and magnesium hydroxide (sodium bicarbonate, calcium carbonate, and magnesium hydroxide are each about 0.1 mEq / mg proton pump inhibitor) Present at a concentration of ~ 5 mEq / mg proton pump inhibitor).

  Also provided herein is a pharmaceutical formulation comprising at least one soluble antacid. Soluble antacids are useful for making uniform suspension formulations. This is because insoluble antacids may settle over time if they do not form a colloidal suspension. For example, in one embodiment, the antacid is sodium bicarbonate and is present at a concentration of about 0.1 mEq / mg proton pump inhibitor to about 5 mEq / mg proton pump inhibitor. In another embodiment, the antacid is a mixture of sodium bicarbonate and magnesium hydroxide (sodium bicarbonate and magnesium hydroxide are each about 0.1 mEq / mg proton pump inhibitor to about 5 mEq / mg proton pump inhibitor) Present in the concentration of the agent). As used herein, the expression “soluble antacid” refers to an antacid that is soluble in gastrointestinal fluid at least 500 mg / mL, or 300 mg / mL, or 200 mg / mL, or 100 mg / mL. Means.

  In some embodiments of the invention, the antacid is specific in particle size. For example, the average particle size of antacids is up to 20 μm in diameter, or up to 30 μm, or up to 40 μm, or up to 50 μm, or up to 60 μm, or up to 70 μm, or up to 80 μm, or up to 90 μm, or up to 100 μm. There are cases. In various embodiments, the diameter of at least about 70% of the antacid does not exceed 20 μm, or up to 30 μm, or up to 40 μm, or up to 50 μm, or up to 60 μm, or up to 70 μm, or up to 80 μm, or up to 90 μm, or The maximum is 100 μm. In other embodiments, the diameter of at least about 85% of the antacid does not exceed 20 μm, or up to 30 μm, or up to 40 μm, or up to 50 μm, or up to 60 μm, or up to 70 μm, or up to 80 μm, or up to 90 μm, or The maximum is 100 μm.

  In other various embodiments of the invention, the antacid is about 0.1 mEq / mg to about 5 mEq / mg proton pump inhibitor, or about 0.5 mEq / mg to about 3 mEq / mg proton pump inhibitor, or about 0.8 mEq / mg to about 2.5 mEq / mg proton pump inhibitor, or about 0.9 mEq / mg to about 2.0 mEq / mg proton pump inhibitor, or about 0.9 mEq / mg to about 1.8 mEq / mg proton pump inhibitor, or Present in an amount from about 1.0 mEq / mg to about 1.5 mEq / mg proton pump inhibitor, or at least 0.5 mEq / mg proton pump inhibitor.

  In another embodiment, the antacid is present in the pharmaceutical formulation of the invention from about 0.1 mEq to about 15 mEq / mg proton pump inhibitor, or about 0.1 mEq / mg proton pump inhibitor, or about 0.5 mEq / mg. Proton pump inhibitor, or about 1 mEq / mg proton pump inhibitor, or about 2 mEq / mg proton pump inhibitor, or about 2.5 mEq / mg proton pump inhibitor, or about 3 mEq / mg proton pump inhibitor, or About 3.5 mEq / mg proton pump inhibitor, or about 4 mEq / mg proton pump inhibitor, or about 4.5 mEq / mg proton pump inhibitor, or about 5 mEq / mg proton pump inhibitor, or about 6 mEq / mg proton Pump inhibitor, or about 7 mEq / mg proton pump inhibitor, or about 8 mEq / mg proton pump inhibitor, or about 9 mEq / mg proton pump inhibitor, or about 10 mEq / mg proton pump inhibitor, or about 15 mEq / mg proton pump inhibitor To.

  In one embodiment, the antacid is in the pharmaceutical formulation of the invention from about 1 mEq to about 160 mEq per dose, or about 1 mEq, or about 5 mEq, or about 7 mEq, or about 10 mEq per dose. Or about 15 mEq, or about 20 mEq, or about 25 mEq, or about 30 mEq, or about 35 mEq, or about 40 mEq, or about 45 mEq, or about 50 mEq, or about 60 mEq, or about 70 mEq Present in an amount of about 80 mEq, or about 90 mEq, or about 100 mEq, or about 110 mEq, or about 120 mEq, or about 130 mEq, or about 140 mEq, or about 150 mEq, or about 160 mEq. .

  In another embodiment, the antacid is on a weight basis in the composition in an amount greater than about 5 times, greater than about 10 times, or greater than about 20 times the amount of proton pump inhibitor. , Or more than about 30 times, or more than about 40 times, or more than about 50 times, or more than about 60 times, or more than about 70 times, or about 80 times Present in an amount greater than or greater than about 90 times or greater than about 100 times.

  In another embodiment, the amount of antacid present in the pharmaceutical formulation is from 200 mg to 3500 mg. In other embodiments, the amount of antacid present in the pharmaceutical formulation is about 200 mg, or about 300 mg, or about 400 mg, or about 500 mg, or about 600 mg, or about 700 mg, or about 800 mg, or about 900 mg, or about 1000 mg, or about 1100 mg, or about 1200 mg, or about 1300 mg, or about 1400 mg, or about 1500 mg, or about 1600 mg, or about 1700 mg, or about 1800 mg, or about 1900 mg, or about 2000 mg, or about 2100 mg, or about 2200 mg, or about 2300 mg, or about 2400 mg, or about 2500 mg, or about 2600 mg, or about 2700 mg, or about 2800 mg, or about 2900 mg, or about 3000 mg, or about 3200 mg, or about 3500 mg.

Dosage Proton pump inhibitors comply with good medical practice, taking into account each patient's clinical conditions, site of administration, dosing method, dosing schedule, and other factors known to health care professionals. Administered and given. When treating humans, it is important to provide a dosage form that delivers the required therapeutic amount of the drug in vivo and allows the drug to be rapidly utilized by the organism. In addition to the dosage forms described herein, the dosage forms described in US Pat. No. 6,489,346 to Phillips et al. Are incorporated herein by reference.

  The percent of the intact drug absorbed into the bloodstream is the treatment-disorder-effective amount (eg, digestive-disease-effective amount of proton pump inhibitor) after administration of the pharmaceutical composition to the subject It is not strictly important as long as it is absorbed. It is understood that the amount of proton pump inhibitor and / or antacid that is administered to a subject depends on, for example, the subject's sex, general health, diet, and / or body weight.

  Illustratively, when a substituted bicyclic aryl-imidazole is administered to an infant or small animal (such as a dog), administration of a relatively low amount (eg, about 1 mg to about 30 mg) of a proton pump inhibitor can be treated. May result in serum concentrations commensurate with clinical efficacy. If the subject is an adult or large animal (such as a horse), a larger dosage unit, eg about 10 mg, about 15 mg, about 20 mg, about 30 mg, for administration to an adult, is achieved to achieve a therapeutically effective serum concentration. , About 40 mg, about 80 mg, or about 120 mg, and about 150 mg, or about 200 mg, or about 400 mg, or about 800 mg, or about 1000 mg, or about 1500 for administration to adult horses A dose of mg, or about 2000 mg, or about 2500 mg, or about 3000 mg, or about 3200 mg, or about 3500 mg is required.

  In other various embodiments of the invention, the amount of proton pump inhibitor administered to the subject is, for example, about 1-2 mg / kg body weight, or about 0.5 mg / kg body weight, or about 1 mg / kg body weight, or About 1.5 mg / kg body weight, or about 2 mg / kg body weight.

  The therapeutic dose can generally be adjusted to optimize safety and efficacy. Typically, dose-effect relationships revealed by in vitro and / or in vivo studies may initially provide useful guidance regarding the appropriate dose for administration to a subject. Tests involving animal models can generally be used as guidance for effective dosages in the treatment of gastrointestinal disorders or diseases according to the present invention. With respect to treatment protocols, the dose administered should be considered to depend on a number of factors, such as the type of drug being administered, the route of administration selected, the age of the subject, the conditions of the particular subject.

  In various embodiments, the human unit dosage form is about 1 mg to about 120 mg, or about 1 mg, or about 5 mg, or about 10 mg, or about 15 mg, or about 20 mg, or about 30. proton pump inhibition of mg, or about 40 mg, or about 50 mg, or about 60 mg, or about 70 mg, or about 80 mg, or about 90 mg, or about 100 mg, or about 110 mg, or about 120 mg Contains agents.

  In other embodiments of the invention, the pharmaceutical formulation causes a measurable serum concentration of the non-acid degraded proton pump inhibitor to reach about 100 ng / ml or more within about 30 minutes after administration of the pharmaceutical formulation. Administered in an amount. In another aspect of the invention, the pharmaceutical formulation provides a measurable serum concentration of a non-acid-degraded or non-acid responsive proton pump inhibitor within about 15 minutes after administration of the pharmaceutical formulation. It is administered to the subject in an amount that reaches 100 ng / ml or higher. In yet another aspect, the pharmaceutical formulation provides a measurable serum concentration of a non-acid-degraded or non-acid responsive proton pump inhibitor of about 100 ng within about 10 minutes after administration of the pharmaceutical formulation. The dose is administered to the subject in an amount that allows it to reach more than / ml.

  In another aspect of the invention, the composition causes a measurable serum concentration of the proton pump inhibitor to reach about 150 ng / ml or more within about 15 minutes after administration of the composition, and after administration of the composition. For about 15 minutes to about 1 hour, the subject is administered to the subject in an amount that maintains the serum concentration of the proton pump inhibitor above about 150 ng / ml. In yet another aspect of the invention, the composition causes a measurable serum concentration of the proton pump inhibitor to reach about 250 ng / ml or more within about 1 hour after administration of the composition, and the proton pump inhibitor Is administered to the subject in an amount that maintains a serum concentration of about 150 ng / ml or greater for about 15 minutes to about 1 hour after administration of the composition. In another aspect of the invention, the composition causes a measurable serum concentration of the proton pump inhibitor to reach about 350 ng / ml or more within about 15 minutes after administration of the composition, and the proton pump inhibitor The serum concentration is administered to the subject in an amount that maintains about 150 ng / ml or more for about 15 minutes to about 1 hour after administration of the composition. In another aspect of the invention, the composition causes a measurable serum concentration of the proton pump inhibitor to reach about 450 ng / ml or more within about 15 minutes after administration of the composition, and the proton pump inhibitor The serum concentration is administered to the subject in an amount that maintains about 150 ng / ml or more for about 15 minutes to about 1 hour after administration of the composition.

  In another aspect of the invention, the composition causes a measurable serum concentration of the proton pump inhibitor to reach about 150 ng / ml or more within about 30 minutes after administration of the composition, and after administration of the composition. For about 30 minutes to about 1 hour, the subject is administered to the subject in an amount that maintains the serum concentration of the proton pump inhibitor at about 150 ng / ml or greater. In yet another aspect of the invention, the composition causes a measurable serum concentration of the proton pump inhibitor to reach about 250 ng / ml or more within about 30 minutes after administration of the composition, and administration of the composition. About 30 minutes to about 1 hour later, the subject is administered to the subject in an amount that maintains the serum concentration of the proton pump inhibitor above about 150 ng / ml. In another aspect of the invention, the composition causes a measurable serum concentration of the proton pump inhibitor to reach about 350 ng / ml or more within about 30 minutes after administration of the composition, and after administration of the composition. For about 30 minutes to about 1 hour, the subject is administered to the subject in an amount that maintains the serum concentration of the proton pump inhibitor at about 150 ng / ml or greater. In another aspect of the invention, the composition causes a measurable serum concentration of the proton pump inhibitor to reach about 450 ng / ml or more within about 30 minutes after administration of the composition, and after administration of the composition. For about 30 minutes to about 1 hour, the subject is administered to the subject in an amount that maintains the serum concentration of the proton pump inhibitor at about 150 ng / ml or greater.

  In yet another aspect of the invention, the composition has a measurable serum concentration of a non-acid-degraded or non-acid responsive proton pump inhibitor of about 500 within about 1 hour after administration of the composition. It is administered to the subject in an amount that reaches ng / ml or higher. In yet another aspect of the invention, the composition provides a measurable serum concentration of a non-acid-degraded or non-acid-responsive proton pump inhibitor within about 45 minutes after administration of the composition. It is administered to the subject in an amount that reaches ng / ml or higher.

  Compositions contemplated by the present invention provide a therapeutic effect as a proton pump inhibitor at intervals of about 5 minutes to about 24 hours after administration (eg, once a day, twice a day if desired). Can be administered 3 times a day).

  Generally speaking, it is desirable to administer an amount of a compound effective in vivo to achieve a serum level commensurate with a concentration known to be effective for a period effective to induce a therapeutic effect. The determination of such parameters is well known in the art. Such considerations are well known in the art and are described in standard textbooks.

  In one embodiment of the invention, the composition is administered to the subject in an effective amount for a gastrointestinal disorder. That is, the composition is administered in an amount that achieves a therapeutically effective amount of the proton pump inhibitor in the serum of the subject over a period of time that provides the desired therapeutic effect. For explanatory but fasting adults (fasting period is usually at least 10 hours), the composition inhibits a therapeutically effective amount of proton pump in the serum of the subject within about 45 minutes after administration of the composition. Administered to achieve the agent. In another embodiment of the invention, the therapeutically effective amount of the proton pump inhibitor is achieved in the serum of the subject within about 30 minutes after administration of the composition to the subject. In yet another embodiment, the therapeutically effective amount of the proton pump inhibitor is achieved in the serum of the subject within about 20 minutes after administration to the subject. In yet another embodiment of the invention, a therapeutically effective amount of the proton pump inhibitor is achieved in the serum of the subject about 15 minutes after administration of the composition to the subject.

  In another embodiment, greater than about 98% of the drug absorbed into the bloodstream; or greater than about 95% is non-acidolytic or reactive with a non-acid; Or more than about 90% of the drug absorbed into the bloodstream; or more than about 75%; or more than about 50% of the drug is non-acid-degraded or reactive with non-acid It is.

  In other embodiments, the pharmaceutical formulation provides a proton pump inhibitor release profile in the USP dissolution method (in this case, more than about 50% of the proton pump inhibitor is about 2 hours after exposure to gastrointestinal fluid). Or more than about 70% of the proton pump inhibitor is released from the composition within about 2 hours after exposure to gastrointestinal fluid; or 50 of the proton pump inhibitor More than 50% is released from the composition within about 1.5 hours after exposure to gastrointestinal fluid; or more than 50% of the proton pump inhibitor is released within about 1 hour after exposure to gastrointestinal fluid Released from the composition).

Flavoring Agents Because proton pump inhibitors have an inherent bitter taste, in one embodiment of the present invention, one or more flavoring agents are used to improve the mouthfeel of a bitter proton pump inhibitor. The “flavor leadership” criteria used in the development of palatable products are (1) the immediate impact of the identified flavoring agent, and (2) the prompt and balanced flavor. , (3) conformity to oral sensory factors, (4) no “off” flavor, and (5) short aftertaste. See, for example, Worthington, A Matter of Taste, Pharmaceutical Executive (April 2001). The pharmaceutical formulations of the invention are improved over one or more of the above criteria.

  A discrimination test that examines differences between samples and ranks a set of samples for specific characteristics; a scaling test that is used to score specific product attributes such as flavor and appearance; A professional tasting person who evaluates qualitatively; an emotional test that measures the reaction between two products, or measures the degree of preference of a product or a specific attribute, or determines the suitability of a specific attribute ( There are several known methods for determining the effects of taste masking materials, such as affective tests; and any descriptive method used in flavor profiling to obtain an objective description of a product is known in the art. This is the method used.

  Various sensory qualities of pharmaceutical formulations, such as aroma, flavor, character note, and aftertaste, can be measured by tests known in the art. See, for example, Roy et al., Modifying Bitterness: Mechanism, Ingredients, and Applications (1997). For example, the aftertaste of a product can be measured based on a sensory scale of time versus intensity. More recently, modern assays have been developed that inform the person in charge of formulation processing of the bitter taste of a particular substance. Using information known to those skilled in the art, it may be readily determined whether the quality of one or more sensations of the pharmaceutical formulations of the present invention has been improved by the use of taste masking materials.

  The taste of the pharmaceutical formulation is important both to increase patient compliance and to compete with other products used for similar diseases, conditions, and disorders. Taste (especially bitterness) is particularly important in pharmaceutical formulations intended for children. This is because children do not take advantage of the fact that the effect appears promptly, accept that bitterness spreads in their mouths, and are more likely to reject drugs with bad taste. Therefore, masking bitterness is becoming even more important for pharmaceutical formulations for children.

  Flavors useful in the pharmaceutical formulations of the present invention include, for example, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, neotame, banana, bavaroa cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel , Cherries, cherries cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherries, cool citrus, cyclamate, cyclamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger , Glycyrrhizic acid, licorice syrup, grapes, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glycyrrhizinate (MagnaS weet (registered trademark)), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidin DC, neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet (registered trademark) powder, raspberry, Root beer, rum, saccharin, saffron, sorbitol, mint, mint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, saccharin sodium, saccharin, aspartame, neotame, acesulfame potassium, mannitol, tallinn, sylitol, sucralose, sorbitol, Swiss cream, tagatose, tangerine, thaumatin, tutti fruit, vanilla, walnut, watermelon, wild cherries, winter green oil, xylito Or any combination of these flavor ingredients, for example, anise-menthol, cherry-anis, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, Orange-cream, vanilla-mint, and mixtures thereof. In other embodiments, sodium chloride is mixed into the pharmaceutical formulation.

  Based on proton pump inhibitors, antacids, suspending agents, and other excipients, and individual amounts, one skilled in the art will have a product that is optimally flavored to consumer requirements and compliance It seems that the best combination of flavors can be determined. See, for example, Roy et al., Modifying Bitterness: Mechanism, Ingredients, and Applications (1997).

  In other aspects of the invention, additional flavoring materials envisioned are those described in US Pat. Nos. 4,851,226, 5,075,114, and 5,876,759. For other examples of taste masking materials, see, for example, Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa .: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences (Mack Publishing Co. , Easton, Pennsylvania 1975); Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms (Marcel Decker, New York, NY, 1980); and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

  In another aspect, the flavor fraction is, for example, about 98% or less of the total weight of the pharmaceutical composition, about 95% or less, about 90% or less, about 85% or less, About 80% or less, about 75% or less, about 70% or less, about 65% or less, about 60% or less, about 55% or less, about 50% or less, about 45% or less, about 40% or less, about 35% or less, about 30% or less, about 25% or less, about 20% or less, about 15% or less, about 10 % Or less, about 5% or less, about 2%, or about 1% or less.

  In various embodiments of the invention, the total amount of flavoring agent present in the pharmaceutical formulation is less than 20 grams, or less than 15 grams, or less than 10 grams, or less than 8 grams, or less than 5 grams, or less than 4 grams, or <3.5 grams, or <3 grams, or <2.5 grams, or <2 grams, or <1.5 grams, or <1 gram, or <500 mg, or <250 mg, or <150 mg, or <100 mg, or Less than 50 mg.

Suspension Administration Suspensions can be used to provide drugs to a patient in liquid form. This type of formulation is particularly important for patients who have difficulty swallowing solid dosage forms. The present invention is directed to a subject for oral administration in the form of a suspension, at least one proton pump inhibitor, at least one antacid, at least one suspension, and at least A pharmaceutical formulation comprising one flavor is provided.

In formulating the pharmaceutical formulations of the present invention, one skilled in the art will select excipients that allow for the generation and maintenance of a uniform suspension. Two examples of a general class of excipients that have been found to yield uniform suspensions that do not readily “settling” in the short time from composition to administration are given below.
Suspending agent: Suspension homogeneity is brought about by reducing the sedimentation of suspended omeprazole particles by increasing the viscosity by the suspending agent; and / or wetting agent: during the composition of the suspension , May increase the initial moisture content of the dry powder and help prevent particle agglomeration or condensation in the suspension.

  Suspensions envisioned for use in the present invention include, for example, polyvinylpyrrolidone (eg, polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30); polyethylene glycol (eg, the molecular weight of polyethylene glycol is about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400); sodium alginate; gums (eg, tragacanth gum and acacia gum; guar gum; xanthan including xanthan gum); sugars; cellulosic materials (Eg, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, etc.); polysorbate-80; polyethoxylated sorbitan monolaurate; povidone; (Such as Avicel PH101 and Avicel CL-161) microcrystalline cellulose; Ragenan, poloxamer F127; maltol magnesium aluminum silicate, there are compounds such as Carbopol (carbopol) 974P.

  Various embodiments of the invention are at least about 2 mg, or at least about 5 mg, or at least about 7 mg, or at least about 10 mg, or at least about 13 mg, or at least about 15 mg, or at least about 20 mg, or At least about 25 mg, or at least about 30 mg, or at least about 35 mg, or at least about 40 mg, or at least about 45 mg, or at least about 50 mg, or at least about 55 mg, or at least about 60 mg, or at least about 65 mg, or at least about 70 mg, or at least about 75 mg, or at least about 80 mg, or at least about 85 mg, or at least about 90 mg, or at least about 95 mg, or at least about 100 mg, or at least about 110 mg Or at least about 120 mg or less Including suspensions of about 130 mg or at least about 140 mg, or at least about 0.99 mg,.

  Provided herein are formulations in which the suspending agent is natural rubber. In some embodiments, the suspending agent is xanthan gum or guar gum or gum arabic (also known as Gum Acacia, Turkey Gum, Gum Senegal).

  Wetting agents contemplated for use in the present invention include oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan mono There are compounds such as laurate, sodium oleate, and sodium lauryl sulfate.

Provided herein are pharmaceutical formulations in which the dosage form is a suspension powder and a substantially homogeneous suspension is obtained upon mixing with water. The suspension is “substantial” after at least about 5 minutes of mixing the pharmaceutical formulation with water, if the suspension is completely divided into any of the upper, middle, and lower layers. To be “uniform”:
(A) in each category is a proton pump inhibitor of at least about 85% of the indicated amount; and / or (b) the variation in% indicated value between the categories is less than about 10%.

  In various aspects of the invention, flocculants are also used.

  In some embodiments, the suspension has a concentration variation between samples taken from two or more points of the suspension that is less than about 25% to about 0.1%, or less than about 20% to about 1 %, Or less than about 15% to about 1%, or less than about 10% to about 1%, or less than about 25%, or less than about 20%, or less than about 15%, or less than about 13%, or about 11% Less than, or less than about 9%, or less than about 7%, or less than about 5%, or less than about 3%, or less than about 1%, or less than about 0.5%, or less than about 0.1%. Overall, it is determined to contain approximately the same concentration of proton pump inhibitor.

  In various embodiments, the amount of variation in proton pump inhibitor concentration found between samples taken from various locations in the suspension is about 25%, or about 22.5%, or about 20%, or about 19%. Or about 18%, or about 17%, or about 16%, or about 15%, or about 14%, or about 13%, or about 12%, or about 11%, or about 10%, or about 9% Or about 8%, or about 7%, or about 6%, or about 5%, or about 4%, or about 3%, or about 2%, or about 1%, or about 0.5%, or about 0.1% It is.

  The concentration of the entire suspension at various points can be determined by any suitable means known in the art, such as, for example, the methods described herein. For example, one suitable method for determining the concentration at various points divides the suspension into three substantially equal sections (upper layer, middle layer, and lower layer). These layers are divided so that they begin at the top of the suspension and end at the bottom of the suspension. In other examples, any number of categories suitable for determining suspension homogeneity, such as 2 segments, 3 segments, 4 segments, 5 segments, or 6 or more segments, may be used. Can be used. Segments can be in a position-related manner (eg top, middle, bottom), numbers (eg 1, 2, 3, 4, 5, 6, etc.) or letters (eg A, B, C, D, E, F) , G, etc.) can be named in any suitable manner. The sections can be divided in any suitable arrangement. In one embodiment, the sections are divided from top to bottom. In this way, it is possible to compare the upper and lower sections to determine whether the proton pump inhibitor settles in the lower section and to determine how fast it is. It becomes possible. Samples can be taken from each section (separation of physical sections may or may not actually be performed). Suitable for determining suspension homogeneity, e.g., all categories, 90% of categories, 75% of categories, 50% of categories, 30% of categories, or any other suitable number of categories, Any number of assigned categories can be evaluated.

  The concentration is readily determined by methods known in the art. For example, the concentration can be determined by a percent label claim. “Percent display (%)” is calculated using the actual amount of proton pump inhibitor per sample compared to the intended amount of proton pump inhibitor per sample. . The intended amount of proton pump inhibitor per sample is the proton expressed based on the formulation protocol or, for example, the “labeled amount”, ie, labeling according to rules recommended by the US Food and Drug Administration. It can be determined in any other suitable manner by reference to the intended amount of pump inhibitor.

  In one embodiment, the suspension is divided into segments, and the percent display amount is determined for each segment. In another aspect, a suspension is determined to be substantially uniform if the suspension includes an amount that is at least close to a set threshold percentage display amount throughout the assessment segment. The suspension assessment category has any set threshold percentage indication suitable for determining that the suspension is substantially uniform. In various embodiments, the category is, for example, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 87%, at least about 88%, at least about 89% of the indicated amount of proton pump inhibitor. %, At least about 90%, at least about 93%, at least about 95%, at least about 98%, at least about 100%, at least about 105%, at least about 110%, or at least about 115%. (E.g., about 80% to about 115%, about 85% to about 110%, about 87% to about 108%, about 89% to about 106% of the indicated amount of proton pump inhibitor) %, Or about 90% to about 105%).

  In some embodiments, after 5 minutes of mixing the pharmaceutical formulation and water, if the suspension is physically or visually completely divided into equal upper, middle and lower segments, each segment Is present in at least about 90%, or at least about 95%, or at least about 98% of the indicated amount of proton pump inhibitor.

  In one embodiment, after at least about 10 minutes of mixing the pharmaceutical formulation and water, each of the suspensions is physically or visually divided into equal upper, middle, and lower segments, each In the segment, there is at least about 80%, or at least about 85%, or at least about 87%, or at least about 90% of the indicated amount of proton pump inhibitor. In another embodiment, after at least about 15 minutes of mixing the pharmaceutical formulation and water, if the suspension is completely divided into equal upper, middle and lower segments, each segment includes a proton pump There is at least about 80% of the indicated amount of inhibitor; or at least about 85%; or at least about 87%; or at least about 90%. In yet another embodiment, if the suspension is physically or visually divided completely into equal upper, middle and lower segments after at least about 30 minutes of mixing the pharmaceutical formulation and water. , Each segment has at least about 80% of the indicated amount of proton pump inhibitor; or at least about 85%; or at least about 87%; or at least about 90%. In still other embodiments, if the suspension is physically or visually divided completely into equal upper, middle and lower segments after at least about 45 minutes of mixing the pharmaceutical formulation and water. , Each segment has at least about 80% of the indicated amount of proton pump inhibitor; or at least about 85%; or at least about 87%; or at least about 90%. In yet another embodiment, after at least about 1 hour of mixing the pharmaceutical formulation and water, the suspension is physically or visually divided completely into equal upper, middle, and lower layers. In each case, there is at least about 70% of the indicated amount of proton pump inhibitor in each section; or or at least about 80%; or at least about 85%; or at least about 87%; or at least about 90%. In other embodiments, if at least about 2 hours after mixing the pharmaceutical formulation and water, the suspension is physically or visually divided completely into equal upper, middle and lower segments, In each section, there is at least about 70% of the indicated amount of proton pump inhibitor; or at least about 80%; or at least about 85%; or at least about 87%; or at least about 90%.

  In other embodiments, if at least about 10 minutes after mixing the pharmaceutical formulation and water, the suspension is physically or visually divided completely into equal upper, middle and lower segments, In each section, there are about 85% to about 99% of the indicated amount of proton pump inhibitor. In another embodiment, after at least about 15 minutes of mixing the pharmaceutical formulation and water, if the suspension is physically or visually divided completely into equal upper, middle and lower segments, In each section, there are about 85% to about 99% of the indicated amount of proton pump inhibitor. In yet another embodiment, if the suspension is physically or visually divided completely into equal upper, middle and lower segments after at least about 30 minutes of mixing the pharmaceutical formulation and water. In each category, there are about 85% to about 99% of the indicated amount of proton pump inhibitor. In yet another embodiment, if the suspension is physically or visually divided completely into equal upper, middle and lower segments after at least about 45 minutes of mixing the pharmaceutical formulation and water. In each category, there are about 85% to about 99% of the indicated amount of proton pump inhibitor. In yet other embodiments, if the suspension is physically or visually divided completely into equal upper, middle and lower segments after at least about 2 hours of mixing the pharmaceutical formulation and water. In each category, there are about 85% to about 99% of the indicated amount of proton pump inhibitor.

  In another embodiment, the% indicated amount of proton pump inhibitor in each category is up to about 5 minutes, up to about 10 minutes, up to about 15 minutes, up to about 30 minutes, up to about 45 minutes, or up to about 1 hour, or up to about 1.5 hours, or up to about 2 hours, or up to about 2.5 hours, or up to about 3 hours, or up to about 3.5 hours, or up to about 4 hours, or up to about 4.5 hours, or up to about 5 hours Across the same. A category is “substantially the same” if the percent display of the proton pump inhibitor does not change by more than 10%.

  In another embodiment, the% indicated amount of proton pump inhibitor in each category is up to about 5 minutes, up to about 10 minutes, up to about 15 minutes, up to about 30 minutes, up to about 45 minutes, or up to about 1 hour, or up to about 1.5 hours, or up to about 2 hours, or up to about 2.5 hours, or up to about 3 hours, or up to about 3.5 hours, or up to about 4 hours, or up to about 4.5 hours, or up to about 5 hours Does not change up to about 20%.

  In yet another aspect, a suspension is determined to be substantially uniform if the suspension contains a variation of a percentage amount less than a set percentage variation for the entire assessment category. . Suspension assessment categories are, for example, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 17%, less than about 15%, less than about 13%, Suitable for determining that a suspension is substantially uniform, such as less than about 11%, less than about 10%, less than about 8%, less than about 5%, less than about 2%, or about 0% variation , The percentage display amount may show less than any set percentage variation.

  In some embodiments, after at least about 5 minutes of mixing the pharmaceutical formulation and water, the suspension is physically or visually completely divided into equal upper, middle, and lower layers. The variation in the percentage value displayed between categories is less than about 10%, or less than about 8%, or less than about 5%, or less than about 3%, or less than about 1%, or less than about 0.1%.

  In one embodiment, after at least about 10 minutes of mixing the pharmaceutical formulation and water, if the suspension is physically or visually completely divided into equal upper, middle and lower segments, Variations in percentage values between categories are less than about 20%, or less than about 15%, or less than about 12%, or less than about 10%, or less than about 8%, or less than about 5%, or about 2%. Less than, or less than about 1%, or less than about 0.5%, or less than about 0.3%, or less than about 0.1%. In another embodiment, after at least about 15 minutes of mixing the pharmaceutical formulation and water, if the suspension is physically or visually divided completely into equal upper, middle and lower segments, Variations in percentage values between categories are less than about 20%, or less than about 15%, or less than about 12%, or less than about 10%, or less than about 5%, or less than about 2%, or about 1%. Less than, or less than about 0.5%, or less than about 0.3%, or less than about 0.1%. In yet another embodiment, if the suspension is physically or visually divided completely into equal upper, middle and lower segments after at least about 30 minutes of mixing the pharmaceutical formulation and water. The variation in percentage value between categories is less than about 20%, or less than about 15%, or less than about 12%, or less than about 10%, or less than about 5%, or less than about 2%, or about 1 %, Or less than about 0.5%, or less than about 0.3%, or less than about 0.1%. In yet another embodiment, if the suspension is physically or visually divided completely into equal upper, middle and lower segments after at least about 45 minutes of mixing the pharmaceutical formulation and water. The variation in% display value between categories is less than about 20%, or less than about 15%, or less than about 10%, or less than about 5%, or less than about 2%, or less than about 1%, or about 0.5. %, Or less than about 0.3%, or less than about 0.1%. In yet another embodiment, the suspension is physically or visually divided into equal upper, middle and lower segments at least about 1 hour after mixing the pharmaceutical formulation and water. In some cases, the variation in percentage value between categories is less than about 20%, or less than about 15%, or less than about 10%, or less than about 5%, or less than about 2%, or less than about 1%, or Less than about 0.5%, or less than about 0.3%, or less than about 0.1%.

  In other embodiments of the invention, at least 30 minutes, or at least 1 hour, or at least 1.5 hours, or at least 2 hours, or at least 2.5 hours, or at least 3 hours, or at least 3.5 hours, or After at least 4 hours, or at least 4.5 hours, or at least 5 hours, there is less than about 10% variation in the percent display value between the categories.

  Typically, the composition remains substantially uniform and does not change for an appropriate time corresponding to the intended use of the composition. In various embodiments, an appropriate time corresponding to the intended use is, for example, at least about 5 minutes, at least about 10 minutes, at least about 15 minutes, at least about 20 minutes, at least about 30 minutes, at least about 30 minutes after mixing with water. 45 minutes, at least about 60 minutes, at least about 75 minutes, at least about 90 minutes, at least about 105 minutes, at least about 120 minutes, at least about 150 minutes, at least about 180 minutes, at least about 210 minutes, at least about 4 hours, at least about 5 hours or more than about 5 hours.

  In one embodiment, the suspension remains substantially uniform for about 5 minutes to about 5 hours after mixing with water. In other embodiments, the suspension, after mixing with water, is at least about 15 minutes to about 45 minutes, at least about 15 minutes to about 1.5 hours, at least about 15 minutes to about 3 hours, at least about 30 minutes to about 1 hour, at least about 30 minutes to about 2 hours, at least about 30 minutes to about 3 hours, at least about 1 hour to about 2 hours, at least about 1 hour to about 3 hours, and at least about 1 hour to about 5 hours, substantially Remains uniform.

  In one embodiment, the composition remains substantially uniform at least until a suspension is prepared for administration to a patient. The suspension can be prepared for administration to a patient at any point after mixing, so long as the suspension is substantially homogeneous. In one embodiment, the suspension is prepared for administration to a patient from any point after mixing until the suspension loses homogeneity. For example, the suspension can be administered to a patient within about 5 minutes after mixing with water, within about 10 minutes, within about 15 minutes, within about 20 minutes, within about 30 minutes, Within about 45 minutes, within 60 minutes, within 75 minutes, within 90 minutes, within 105 minutes, within 120 minutes, within 150 minutes, within 180 minutes, within 210 minutes It can be prepared within minutes, within about 4 hours, within about 5 hours, or after about 5 hours.

  In another embodiment, the suspension is prepared for administration to a patient within about 5 minutes to about 2 hours after mixing. In yet another embodiment, the suspension is prepared for administration to a patient within about 15 minutes to about 1 hour after mixing. In yet another embodiment, the suspension is prepared for administration to a patient within about 2 hours after mixing.

  In some preferred embodiments, the pharmaceutical formulation comprises a gum suspension. In another aspect, the composition comprises omeprazole, sodium bicarbonate, and xanthan gum. In yet another aspect, the composition comprises omeprazole, sodium bicarbonate, xanthan gum, and at least one flavoring agent.

  In another embodiment, upon administration to a subject, the composition contacts the gastrointestinal fluid of the stomach, prevents the pH of the gastrointestinal fluid, prevents acid degradation of the proton pump inhibitor in the gastrointestinal fluid of the stomach, or Increasing the pH to inhibit allows proton pump inhibitors with measurable serum concentrations to be absorbed into the subject's serum, thereby allowing pharmacokinetic and pharmacodynamic parameters to Can be obtained by a known examination procedure.

Compositions The pharmaceutical formulations of the present invention comprise the desired amount of proton pump inhibitor, antacid, suspending agent, and flavoring agent and include, for example, sterilized packaged powders, single use powders, And may take the form of a powder such as an expandable powder. Such pharmaceutical preparations of the present invention can be produced by conventional pharmacological techniques.

  Conventional pharmacological techniques include, for example, one or a combination of (1) dry mixing, (2) wet granulation, (3) milling, and (4) dry or non-aqueous granulation. . See, for example, Lachman et al., The Theory and Practice of Industrial Pharmacy (1986). These methods, as well as other suitable methods, are known to those skilled in the art.

  In one embodiment, the proton pump inhibitor is microencapsulated prior to formulation into one of the above dosage forms. In another embodiment, some or all of the antacid is also microencapsulated prior to further formulation into one of the above dosage forms. In some embodiments, the microencapsulating material is used to extend the shelf life of the pharmaceutical formulation. In other embodiments, the microencapsulation material is a cellulose hydroxypropyl ether (HPC) such as Klucel®, Nisswo HPC, and PrimaFlo HP22; a low substituted hydroxypropyl ether (L-HPC); a cellulose hydroxypropyl Methyl ether (HPMC) (such as Seppifilm-LC, Pharmacoat®, Metolose SR, Opadry YS, PrimaFlo, MP3295A, Benecel MP824, and Benecel MP843); methylcellulose polymers (Methocel®, and Metolose®) Ethyl acetate (EC) and mixtures with E461, Ethocel®, Aqualon®-EC, Surelease, etc .; polyvinyl alcohol (PVA) (such as Opadry AMB); hydroxyethyl cellulose (Natrosol®) Carboxymethylcellulose and carboxymethylcellulose salt (CMC) (Aualon (Registered trademark) -CMC, etc.) copolymer of polyvinyl alcohol and polyethylene glycol (such as Kollicoat IR (registered trademark)); monoglyceride (Myverol), triglyceride (KLX), polyethylene glycol, modified food starch, Acrylic polymers and mixtures of acrylic polymers and cellulose ethers (such as Eudragit® EPO, Eudragit® RD 100, and Eudragit® E100); cellulose acetate phthalate; sepifilm (HPMC and stearic acid) A mixture of these materials, cyclodextrins, and mixtures of these materials). In yet another embodiment, an antacid such as sodium bicarbonate is mixed with the microencapsulation material. In another embodiment, an antioxidant is mixed into the microencapsulation material. In yet another embodiment, a plasticizer is mixed into the microencapsulation material.

  In another embodiment, the film coating is applied to the surface of the pharmaceutical formulation by standard coating procedures as described in Remington's Pharmaceutical Sciences, 20th edition, (2000).

  As used herein, (a) coating at least a portion of at least one antacid with at least a portion of a micronized proton pump inhibitor to obtain a first blend; and (b) a first (A) at least one acid labile micronized proton pump inhibitor made by a method comprising dry blending a blend of with at least one other excipient; and (b) A pharmaceutical formulation comprising at least one antacid is provided. The expression “coating” means the step of contacting at least a portion of the micronized proton pump inhibitor with the surface of at least a portion of the antacid. Although the antacid particles can be completely covered by micronized omeprazole to form a “shell-like coating”, the use of the expression “coating” is not intended to refer only to this case. For example, in many cases, micronized omeprazole coats only a portion of the antacid, leaving a portion of the surface of the antacid particles uncoated. As shown in FIG. 1, micronized omeprazole or PPI may be adsorbed to an antacid. While not wishing to be bound by theory, it is believed that PPI attaches to antacids via electrostatic or Van der Waals interactions. Such a transient coating can be peeled off by applying an external force such as a vacuum transfer of “coated” material.

  In other embodiments, the pharmaceutical formulation further comprises a pharmaceutically compatible carrier, binder, filler, suspending agent, flavoring agent, sweetening agent, disintegrant, surfactant, preservative, lubricant, coloring. Agent, diluent, solubilizer, humidifier, stabilizer, wetting agent, flocculant, anti-adhesive agent, wall cell activator, antifoam agent, antioxidant agent, chelating agent, antifungal agent, antibacterial agent, Or one or more additional materials, such as one or more combinations thereof.

(A) Particle size The particle size of proton pump inhibitors, antacids, and excipients can affect bioavailability, blend uniformity, separation, and fluidity It is an important factor. In general, smaller particle size drugs have a higher surface area, which increases the rate of bioabsorption of the drug and significantly reduces water solubility. The size of the drug and excipient particles may also affect the suspendability of the pharmaceutical formulation. For example, smaller particles are less likely to settle and a good suspension will be obtained.

  In various embodiments, the average particle size of the dry powder is less than about 500 microns in diameter, or less than about 450 microns in diameter, or less than about 400 microns in diameter, or less than about 350 microns in diameter, or Less than about 300 microns, or less than about 250 microns in diameter, or less than about 200 microns in diameter, or less than about 150 microns in diameter, or less than about 100 microns in diameter, or less than about 75 microns in diameter, or about 50 in diameter Less than a micron, or less than about 25 microns in diameter, or less than about 15 microns in diameter. In other embodiments, the average particle size of the aggregate is from about 25 microns in diameter to about 300 microns in diameter. In yet another embodiment, the average particle size of the aggregate is about 25 microns in diameter to about 150 microns in diameter. In yet another embodiment, the average aggregate particle size is from about 25 microns in diameter to about 100 microns in diameter. The expression “average particle size” means the average diameter of particles and / or aggregates used in a pharmaceutical formulation.

  In another aspect, the average particle size of the insoluble excipient is from about 5 μm to about 500 μm, or less than about 400 μm, or less than about 300 μm, or less than about 200 μm, or less than about 150 μm, or less than about 100 μm, Or less than about 90 μm, or less than about 80 μm, or less than about 70 μm, or less than about 60 μm, or less than about 50 μm, or less than about 40 μm, or less than about 30 μm, or less than about 25 μm, or less than about 20 μm, or less than about 15 μm, Or less than about 10 μm, or less than about 5 μm.

  In other embodiments of the invention, the particle size of at least about 80% of the dry powder particles is less than about 300 μm, or less than about 250 μm, or less than about 200 μm, or less than about 150 μm, or less than about 100 μm, or about 500 μm. Is less than. In another aspect, the particle size of at least about 85% of the dry powder particles is less than about 300 μm, or less than about 250 μm, or less than about 200 μm, or less than about 150 μm, or less than about 100 μm, or less than about 50 μm. . In still other embodiments of the invention, the particle size of at least about 90% of the dry powder particles is less than about 300 μm, or less than about 250 μm, or less than about 200 μm, or less than about 150 μm, or less than about 100 μm, or about It is less than 50 μm. In yet another aspect, the particle size of at least about 95% of the dry powder particles is less than about 300 μm, or less than about 250 μm, or less than about 200 μm, or less than about 150 μm, or less than about 100 μm, or less than about 50 μm. is there.

  In another embodiment, the particle size of the other excipient is selected to be approximately the same as the particle size of the antacid. In yet another aspect, the particle size of the insoluble excipient is selected to be approximately the same as the particle size of the proton pump inhibitor.

  Several factors can be considered when selecting both the appropriate excipients and their amounts. For example, the excipient should be pharmaceutically acceptable. Also, in some examples, rapid dissolution and neutralization of gastric acid is performed to maintain gastric pH at about 6.5 for at least 1 hour. The excipient (if any) that contacts the proton pump inhibitor should also be chemically compatible with the proton pump inhibitor. The expression “chemically compatible” means that the degradation of the material is less than 10% of the proton pump inhibitor when stored at room temperature for at least about 1 year.

  Mural cell activators are administered in an amount sufficient to produce the desired promoting effect without causing undesirable side effects in the patient. In one embodiment, the mural cell activator is administered in an amount of about 5 mg to about 2.5 g per 20 mg dose of proton pump inhibitor.

(B) Exemplary Powder Compositions The powders described herein are bulk blend compositions comprising a proton pump inhibitor, one or more antacids, suspending agents, and pharmaceutical excipients mixed together. It can be prepared by forming a product. When such a bulk blend composition is said to be homogeneous, proton pump inhibitors, antacids, suspending agents, and excipients are evenly dispersed throughout the composition, and thus the composition Means that it can be easily subdivided into equally effective unit dosage forms. Individual unit doses may include a film coating that degrades in contact with the diluent.

  In various embodiments, the proton pump inhibitor, the antacid, and optionally one or more excipients are dry blended within about 5 minutes, less than about 10 minutes, less than about 20 minutes, Compressed into a mass such as a tablet with sufficient hardness to become a pharmaceutical composition that substantially disintegrates in water in less than about 30 minutes, in less than about 40 minutes, in less than about 50 minutes, or in less than about 60 minutes Is done. When at least 50% of the pharmaceutical composition is disintegrated, the compacted mass is effectively disintegrated.

  The suspension powder can be prepared by mixing a finely divided proton pump inhibitor, an antacid, and a suspending agent. In various embodiments, the powder may include one or more pharmaceutical excipients.

  Effervescent powder is also prepared according to the present invention. Effervescent salts are used to disperse pharmaceuticals in water for oral administration. Effervescent salts are granules or coarse powders that contain a pharmaceutical in a dry mixture and usually contain sodium bicarbonate, citric acid, and / or tartaric acid. When water is added to the salt of the present invention, the acid and base react to release carbon dioxide gas, resulting in “foaming”. Examples of effervescent salts include ingredients such as sodium bicarbonate, or a mixture of sodium bicarbonate and sodium carbonate, citric acid, and / or tartaric acid. Any acid and base combination that leads to the release of carbon dioxide can be combined with sodium bicarbonate, citric acid and tartaric acid as long as the ingredients are suitable for pharmaceutical use and the pH is about 6 or higher. Can be used instead.

(C) Exemplary Solid Compositions Solid compositions, such as tablets, chewable tablets, effervescent tablets, and capsules, contain microencapsulated proton pump inhibitors with one or more antacids and pharmaceutical additives. It is prepared by mixing with a form to form a bulk blend composition. When such a bulk blend composition is said to be uniform, the microencapsulated proton pump inhibitor and the antacid are uniformly dispersed throughout the composition, so that the composition can be It means that it can be easily divided into equally effective unit dosage forms, such as drugs and capsules. Individual unit dosage forms may include a film coating that disintegrates upon oral ingestion or upon contact with a diluent.

  Compressed tablets are solid dosage forms prepared by compressing the bulk blend composition described above. In various embodiments, the compressed tablets of the present invention include one or more flavoring agents. In other embodiments, the compressed tablet includes a film that covers the surface of the final compressed tablet. In other embodiments, the compressed tablets include one or more excipients and / or flavoring agents.

  Capsules can be prepared, for example, by filling the bulk blend composition described above inside the capsule.

  Chewable tablets can be prepared by compressing the above-described bulk blend composition. In one embodiment, the chewable tablet comprises a material useful for extending the shelf life of the pharmaceutical formulation. In another aspect, the microencapsulated material has taste masking properties. In various other embodiments, the chewable tablet comprises one or more flavoring agents and one or more taste masking materials. In yet other embodiments, the chewable tablet comprises both a material useful for extending the shelf life of the pharmaceutical formulation and one or more flavoring agents.

  In various embodiments, the microencapsulated proton pump inhibitor, antacid, and optionally one or more excipients are dry blended and less than about 30 minutes, less than about 35 minutes after oral administration, Pharmaceuticals that release antacids and proton pump inhibitors into the gastrointestinal fluid by substantially disintegrating in less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes Compressed into a mass, such as a tablet, having sufficient hardness to provide a functional composition. When at least 50% of the pharmaceutical composition is disintegrated, the compacted mass is effectively disintegrated.

Treatment
Initial treatment of a subject with a disease, condition, or disorder for whom treatment with an inhibitor of H ⁺ / K ⁺ -ATPase is indicated can be initiated at the dosages described above. Treatment is generally continued for a period of hours, days, or weeks to months or years as needed until the disease, condition, or disorder is managed or eliminated. Subjects who are treated with the compositions disclosed herein generally receive monitoring by any method known in the art to determine the effectiveness of the treatment. Continuous analysis of such data allows for modification of the treatment procedure during treatment, allows the optimal effective amount of the compounds of the invention to be administered at any time, and also determines the duration of treatment. It becomes. In this way, the treatment procedure / dosage schedule should be such that the lowest amount of an inhibitor of H ⁺ / K ⁺ -ATPase that is sufficiently effective is administered, and that the administration is not a disease, condition, or disorder. It may be reasonably modifiable during treatment to continue only as long as necessary to successfully treat.

  In one embodiment, the pharmaceutical formulation is useful for the treatment of a condition, disease or disorder for which treatment with a proton pump inhibitor is indicated. In other embodiments, the method of treatment comprises oral administration of one or more compositions of the present invention to a subject in need of treatment in an amount effective to treat the condition, disease or disorder. In another aspect, the disease, condition, or disorder is a gastrointestinal disease. The administration procedure in preventing, ameliorating, or ameliorating the pain caused by a disease, condition, or disorder can be varied to take into account various factors. Such factors include subject type, age, weight, sex, diet, and medical condition, as well as the severity of the disorder or disease. Thus, the administration procedure actually used can vary considerably and can therefore deviate significantly from the administration procedure described herein.

  In some embodiments, the pharmaceutical formulation is administered after a meal. In another embodiment, the pharmaceutical formulation administered after a meal is in the form of a chewable tablet.

  The present invention relates to a method of treating, preventing, reversing, stopping, or delaying progression of a gastrointestinal disease clinically manifested by administering the composition of the present invention to a subject, or a gastrointestinal disease Also included are methods of treating symptoms associated with or associated with. The subject may already have gastrointestinal disease at the time of administration and may be at risk of developing gastrointestinal disease. The symptoms or conditions of a subject's gastrointestinal disease can be determined by those skilled in the art and are described in standard textbooks. Such methods include orally administering to a subject in need of treatment an effective amount of a gastrointestinal disorder of one or more compositions of the present invention.

  Gastrointestinal diseases include, for example, duodenal ulcer disease, gastrointestinal ulcer disease, gastroesophageal reflux disease, erosive esophagitis, hyporeactive symptomatic gastroesophageal reflux disease, pathologic gastrointestinal hypersecretion disease, Zollinger- There are Ellison syndrome and high acid dyspepsia. In one embodiment of the invention, the gastrointestinal disorder is heartburn.

  In addition to being useful for human treatment, the present invention applies to other subjects such as animals, reptiles, birds, rare animals, and farm-raised animals including mammals and rodents that are targeted by veterinarians. Is also useful. Mammals include primates such as monkeys or lemurs, horses, dogs, pigs or cats. Rodents include rats, mice, squirrels, or guinea pigs.

  In various aspects of the invention, the composition releases the proton pump inhibitor into the transport site (typically the stomach) while substantially preventing or inhibiting acid degradation of the proton pump inhibitor. Designed to enable.

  The pharmaceutical composition of the present invention is, for example, an antibacterial agent, alginate, motor function improving agent, H2 antagonist, antacid that is commonly administered to minimize pain and / or complications associated with digestive disorders. It can also be used in combination with an agent or another pharmaceutical agent indicated to treat or prevent the disease, such as sucralfate ("combination therapy").

  Combination therapy envisaged in the present invention treats gastrointestinal disorders of the pharmaceutical formulation of the present invention in combination with another pharmaceutically active agent indicated for treatment or prevention of gastrointestinal disorders in a subject Thus, it includes administration as part of a specific therapeutic procedure intended to provide beneficial effects from the synergistic action of these agents. The beneficial effects provided by the combination include, but are not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents. Administration of such therapeutic agents typically involves a period of time (usually substantially, simultaneously, minutes, hours, days, weeks, months, depending on the combination selected) Or for several years).

  The combination therapy of the present invention allows for continuous administration of the target therapeutic agent, that is, each therapeutic agent is administered at various times, and administration of these therapeutic agents, or at least two therapeutic agents. Are also contemplated to be administered substantially simultaneously. Substantially simultaneous administration can be achieved, for example, by administering to a subject one tablet or capsule containing each therapeutic agent in a fixed ratio, or multiples thereof. Sequential or substantially simultaneous administration of individual therapeutic agents can be performed by any suitable route.

  The composition of the present invention can be administered orally or nasogastrically, and other therapeutic agents used in combination include oral route, transdermal route, intravenous route, intramuscular route. Administration can be by any suitable route for a particular agent, but not limited to, or by direct absorption through mucosal tissue. For example, the composition of the present invention can be administered orally or nasogastrically, and the combined therapeutic agents can be administered orally or transdermally. The order in which the therapeutic agents are administered is not critical. Combination therapies include analgesics such as steroidal or non-steroidal anti-inflammatory drugs, or drugs that improve gastric motility (eg, non-drug therapies, including but not limited to surgery) Other combinations with, but not limited to, other biologically active ingredients may include administration of the therapeutic agents described above.

  The therapeutic compound making up the combination therapy may take the form of a dosage form or may take the form of another dosage form intended for substantially simultaneous administration. The therapeutic compounds making up the combination therapy can be administered sequentially, one by one, along with any of the therapeutic compounds administered by a procedure that requires two-step administration. Thus, certain procedures may require sequential administration of therapeutic compounds one by one, with administration at intervals of another active agent. The time period between multiple administration phases depends on the characteristics of the individual therapeutic compound, such as the potency, solubility, bioavailability, plasma half-life, and kinetic profile of the therapeutic compound, and the intake of food And depending on the effect of the subject's age and conditions, for example, in the range of minutes to hours to days. Circadian variation in target molecule concentration may also determine the optimal dosing interval.

  The therapeutic compound used in the combination therapy envisioned by this invention may be a single type of oral route, whether administered simultaneously, substantially simultaneously, or sequentially one by one. The procedure may involve administration of a therapeutic compound and administration of another therapeutic compound by the oral, transdermal, intravenous, intramuscular route, or by direct absorption, eg, through mucosal tissue. is there. The therapeutic compound used in the combination therapy is administered orally, using inhalation spray, rectally, topically, buccally, sublingually or parenterally (eg subcutaneous, intramuscular, intravenous Such as intradermal injection, or injection method), individually or as a whole, such individual therapeutic compounds are pharmaceutically acceptable excipients, Included in suitable pharmaceutical formulations of diluents or other formulation ingredients.

  In one embodiment, the pharmaceutical formulations of the invention are administered with a low-strength enteric-coated aspirin. In another embodiment, the second active agent (eg, aspirin or NSAID) used in combination with the pharmaceutical formulation of the present invention is enteric coated. In other embodiments, the antacid present in the pharmaceutical formulation of the present invention may increase the pH level of the gastrointestinal fluid so that part or all of the enteric coating on the surface of the second active agent is intragastric. Makes it possible to dissolve.

  For the sake of brevity, all patents and other references cited herein are hereby incorporated by reference in their entirety as if each were incorporated herein in their entirety.

Examples The invention is further illustrated by the following examples, which are not limited in any manner. The experimental procedure for obtaining the described data is detailed below. For any formulation described herein, multiple administrations may be formulated proportionately as is known in the art. Coatings, layers, and encapsulation are applied to conventional methods using equipment commonly used for these purposes.

  It should be understood that the present invention has been described for purposes of illustration and is not intended to be limited to the language used, but is intended to be descriptive in nature.

Example I: Preparation of omeprazole + sodium bicarbonate powder for suspension This example describes the preparation of omeprazole + sodium bicarbonate powder (OSB-PFS) for suspension. Each dose of OSB-PFS contains omeprazole and sodium bicarbonate. Sodium bicarbonate in the OSB-PFS formulation prevents acid degradation of the active ingredient omeprazole in vivo.

  A variety of OSB-PFS has been formulated using the ingredients listed in Table 1:

(Table 1) OSB-PFS composition omeprazole sodium bicarbonate sweetener (group)
Suspension (group)
Flavoring agent (s)

  An exemplary OSB-PFS composition containing 20 mg omeprazole is shown in Table 2.

Table 2: Exemplary OSB-PFS composition (20 mg omeprazole) (mg)

  An exemplary OSB-PFS composition containing 40 mg omeprazole is shown in Table 3.

Table 3 Exemplary OSB-PFS composition (40 mg omeprazole) (mg)

  Exemplary OSB-PFS compositions containing 60 mg omeprazole are shown in Table 4.

TABLE 4 Exemplary OSB-PFS composition (60 mg omeprazole) (mg)

  Omeprazole powder obtained from Union Quimico Farmaceutica S.A. (commonly known as Uquifa) was micronized so that 90% of its maximum diameter was 25 μm. Sodium bicarbonate grade (USP # 1 grade) was chosen to complement the omeprazole particle size to avoid stratification. The particle sizes of other excipients such as sweeteners and suspending agents were also carefully chosen to obtain maximum blend uniformity.

  Omeprazole is a flocculent powder with a low volume density, the main part of the component being denser and larger in particle size. The ingredient level of the active ingredient omeprazole accounted for a relatively low percentage of the total weight. Geometric mixing of omeprazole with a suitable carrier facilitated a uniform omeprazole distribution due to batch balance during the main mixing.

  Because of the extremely low density and stickiness of the flavor premix components, flavor premix was also performed. A small amount of sweetener was mixed with the premix. The material was then mixed for 15 minutes.

Example II: Exemplary formulations containing various flavors Omeprazole and omeprazole / bicarbonate suspensions were evaluated by the Flavor Profile method of sensory analysis. The sample was evaluated according to the following protocol. Four to six trained professional sensory panelists participated in each panel session. All panelists tasted the same sample at the same time. The panelists included a maximum of 3 ml of sample in the mouth for 10 seconds, set an evaluation time and performed tasting, and then removed almost all of the sample from the mouth. There was a 20 minute washout period between samples. During this time, the panelists squeezed using natural water and unsalted crackers.

  Various components were evaluated. Initial flavor and mouth feel attributes were recorded for up to 1 minute. Aftertaste characteristics were recorded 1 minute, 3 minutes, 5 minutes, and 10 minutes after exhalation.

Using this method, the following flavor profile was obtained for omeprazole in water (2 mg / ml).

Using the same method described above, the following flavor profile was obtained for omeprazole / sodium bicarbonate (2 mg / ml) in water.

  After completion, various tablets containing flavor were prepared and examined in a similar manner. Tables 5-11 show 40 mg omeprazole tablets with various flavors.

(Table 5) OSB-PFS composition containing peach flavorant / aspartame

(Table 6) OSB-PFS composition containing peach flavorant / sucralose

Table 7: OSB-PFS composition containing citrus flavorant / sucralose

Table 8: OSB-PFS composition containing citrus flavorant / aspartame

Table 9: OSB-PFS composition containing red fruit flavor / sucralose

Table 10: OSB-PFS composition with red fruit flavorant / aspartame

Table 11: OSB-PFS composition with peach flavorant / sucralose

Example III: The preparation of the final dosage form of omeprazole + sodium bicarbonate powder for suspension consists of the production of “power blend” and two separate stages of filling and packaging each packet of the blend with an automatic filling device. Including.

  The equipment used for the powder mixing stage is as follows: 30 cu. Ft. V-Blender, 4000 liter Scholl-Blender, automatic vibrating sieve (# 20 meshes) for coating micronized PPI on antacid / s) and floor balance.

The powder blend was manufactured in the following steps:
(A) Components were weighed and screened on a 20 mesh screen and then transferred to another polyethylene bag:
(B) Sodium bicarbonate and omeprazole were loaded into a 30 cu. Ft. V-shell blender. This material was blended for 5 minutes. To this mixture was added a portion of xylitol and sucrose and the mixture was blended for 5 minutes. Next, pre-blended omeprazole was removed from the blender and transferred to a display container. The material was then passed through a # 20 mesh s / s sieve and received in another display container. In some experiments, an automatic vibrating screen was used. Next, a portion of sucrose, peppermint flavor, peach flavor, sucralose, and xanthan gum were loaded into a 5 cu. Ft. V-shell blender in the above order. This material was blended for 5 minutes.

  After blending the ingredients, the pre-blended flavor was removed from the blender and transferred to a display container and passed through a # 20 mesh s / s sieve and received in a second display container. In one example, an automatic vibrating screen was used. Next, another portion of sucrose is passed through a # 20 mesh s / s sieve into a display container, and another portion of xylitol is then passed through a # 20 mesh s / s sieve into a display container. I received it. Automatic vibrating sieves may be used.

  The material was then divided into two equal parts. Next, a portion of sodium bicarbonate was passed through a # 20 mesh s / s sieve and received in the display container. The various pre-blended materials were then loaded into a 4000 liter Scholl blender and the materials were blended for 20 minutes. When uniform, the final blend was removed.

Example VI: Suspension of omeprazole + sodium bicarbonate powder for suspension In this example, the suspension of omeprazole + sodium bicarbonate powder for suspension with and without xanthan gum was determined by HPLC. The determination will be described. The results obtained from both physical and chemical studies revealed that xanthan gum is required as a suspending agent in the formulation stage.

  A fixed amount of omeprazole + sodium bicarbonate powder (40 mg) for suspension, corresponding to 30 units, was prepared by mixing the appropriate amount of ingredients described in Example 1.

Three sets of three different samples were prepared with or without xanthan gum and assayed for content homogeneity using a gradient HPLC method with the following chromatographic parameters: Was:
Column: 150 mm x 3.9 mm (using USP L7 (5 μm) packing)
Guard column: 20 mm x 3.9 mm (using USP L7 (5 μm) packing)
Detection: UV light at 280 nm Column temperature: Atmospheric temperature Injection volume: 20μL
Flow rate: 1 mL / min Runtime: 15 minutes Mobile phase: 70:30 (v / v) = phosphate buffer (pH 7.0): acetonitrile Sample dilution: 75:25 (v / v) = 10 mM tetrabo Sodium acid: Acetonitrile

  The percent indicated amount of omeprazole from each sampling location and individual sample was calculated. For each of the three samples in each set, for each suspension sample prepared with or without xanthan gum, the percent display average value and relative standard deviation (RSD), and time point at each position are displayed. 12 and in Table 13.

(Table 12) Summary of suspension test results when xanthan gum was not added

(Table 13) Summary of suspension test results when xanthan gum is added

  Table 14 and Table 15 show the averages and RSDs of the indicated amount% at each position and each time point for suspension samples prepared with or without xanthan gum for each set of 3 samples. Describe.

(Table 14) Summary of suspension test results when xanthan gum was not added

(Table 15) Summary of suspension test results when xanthan gum is added

  From the above results, it can be seen that in the presence of xanthan gum, sufficient suspendability is observed by two separate analyzes up to 3 hours after composition. In the absence of xanthan gum, the suspendability results were low even after only 5 minutes after composition and disintegrated during the 3 hour standing time. By visual observation, the suspension without added xanthan gum (white / off-white) began to settle after 1 hour and more precipitation was observed after 3 hours. For suspensions containing xanthan gum (off-white), no powder precipitation was observed after 1 hour and 3 hours.

  From the results shown in Tables 12 to 15, it can be seen that the suspendability is extremely low in the absence of xanthan gum. This conclusion is also supported by visual observation.

Example V: Adsorption of Omeprazole to a Common Dosing Device This example illustrates that the omeprazole portion of OSB-PFS does not adsorb to a common dosing device.

  Auxiliary devices used to construct and administer OSB-PFS include dosing cups, syringes, and gastric drainage tubes (nasal or oral gastric tubes). A recovery test was conducted to examine the adsorption of OSB-PFS to the gastric drainage tube. In this in vitro test, 20 mL of configured OSB-PFS was passed through an 18F (French) gastric drain and then washed with 20 mL of water. The average omeprazole recovery from this study was greater than 90% omeprazole. Thus, omeprazole does not significantly adsorb to common dosing devices.

Example VI: Omeprazole Formulations and Excipients In addition to the suspending and wetting agents described herein, other exemplary suspending and wetting agents are known in the art. See, for example, Handbook of Pharmaceutical Excipients (2000). The following is a partial list of suspending and wetting agents that list exemplary amounts.

  To select the appropriate suspension, conduct experiments to measure the solubility of the suspension to determine the optimal concentration, the effect of omeprazole on suspendability, and the effect of omeprazole on chemical stability .

Example VII: Exemplary excipients and particle size As described herein, the particle size of the material is important in maintaining the suspension. Examples of excipients that can be used with the micronized proton pump inhibitor are listed below.

  It should be understood that the present invention has been described for purposes of illustration, and that the terms and expressions used are not intended to be limiting, but are intended to be illustrative. All patents and other references cited herein are hereby incorporated by reference in their entirety. Needless to say, many changes, equivalents, and variations in the present invention are possible in view of the above description. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described.

SEM photograph of sodium bicarbonate coated with micronized omeprazole. SEM photo of sodium bicarbonate. SEM photograph of micronized omeprazole.

Claims (43)

(A) at least one acid-labile micronized proton pump inhibitor;
A powdered pharmaceutical formulation for suspension comprising (b) at least one antacid; and (c) at least one suspension that is a gum, substantially by mixing powder and water A pharmaceutical preparation which gives a homogeneous suspension.   Proton pump inhibitors are omeprazole, hydroxyomeprazole, esomeprazole, tenatoprazole, lansoprazole, pantoprazole, rabeprazole, dontoprazole, habeprazole, perprazole, lansoprazole, parisprazole, leminoprazole Or a substituted bicyclic aryl selected from the group consisting of their free bases, free acids, salts, hydrates, esters, amides, enantiomers, isomers, tautomers, polymorphs, or prodrugs The pharmaceutical preparation according to claim 1, which is -imidazole.   The proton pump inhibitor is omeprazole, or a free base, free acid, salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, or prodrug thereof. 1. The pharmaceutical preparation according to 1.   The proton pump inhibitor is esomeprazole, or their free base, free acid, salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, or prodrug, The pharmaceutical preparation according to claim 1.   The proton pump inhibitor is lansoprazole, or a free base, free acid, salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, or prodrug thereof. 1. The pharmaceutical preparation according to 1.   2. The pharmaceutical formulation according to claim 1, wherein the at least one antacid comprises at least one soluble antacid.   2. The pharmaceutical formulation of claim 1, wherein the at least one antacid is present in an amount of at least about 5 mEq.   The pharmaceutical formulation of claim 1, comprising from about 500 mg to about 3000 mg of an antacid.   One or more excipients selected from the group consisting of mural cell activators, organic solvents, erosion enhancers, diffusion enhancers, antioxidants, and binders, disintegrants, fillers, surfactants, 2. The pharmaceutical formulation of claim 1, further comprising a carrier material selected from the group consisting of solubilizers, stabilizers, lubricants, wetting agents, flocculants, diluents, anti-adhesive agents, and antifoaming agents.   The pharmaceutical preparation according to claim 1, wherein the suspension is guar gum.   2. The pharmaceutical preparation according to claim 1, wherein the suspension is xanthan gum.   2. The pharmaceutical formulation of claim 1, comprising from about 5 mg to about 200 mg of at least one gum suspension.   2. The pharmaceutical formulation of claim 1, comprising at least about 30 mg of at least one gum suspension.   The pharmaceutical formulation according to claim 1, comprising at least one flavorant.   Flavors are monoammonium glycyrrhizinate, peach flavor, red fruit flavor, strawberry flavor, cherry flavor, citrus flavor, lemon flavor, lime flavor, peppermint flavor, cotton candy flavor, vanilla and vanillin Selected from the group consisting of flavor, maltol, marshmallow flavor, menthol, anise flavor, sucrose, sucralose, sodium saccharin, saccharin, aspartame, neotame, acesulfame potassium, mannitol, talin, xylitol, sorbitol, and mixtures thereof 15. The pharmaceutical preparation according to claim 14.   15. The pharmaceutical formulation of claim 14, wherein the flavoring agent is a mixture of xylitol, sucrose, sucralose, peach flavoring, and peppermint flavoring.   2. The pharmaceutical formulation of claim 1, wherein the initial serum concentration of the proton pump inhibitor is greater than about 500 ng / ml at any time within about 1 hour after administration of the pharmaceutical formulation.   2. The pharmaceutical formulation of claim 1, wherein the initial serum concentration of the proton pump inhibitor is greater than about 100 ng / ml at any time within about 30 minutes after administration of the pharmaceutical formulation.   2. The pharmaceutical formulation of claim 1, wherein the maximum serum concentration is reached within about 15 minutes after administration of the pharmaceutical formulation.   The pharmaceutical formulation of claim 1, wherein the average particle size of the suspension powder is from about 10 microns to about 200 microns in diameter.   2. The pharmaceutical formulation of claim 1, wherein at least about 80% of the proton pump inhibitor particles are less than about 40 μm.   If the suspension is completely divided into three equal sections, at least about 5 minutes after mixing the pharmaceutical formulation with water, at least about the label claim of the proton pump inhibitor in each section The pharmaceutical formulation according to claim 1, wherein 90% is present.   If the suspension is completely divided into three equal sections, at least about 80% of the indicated amount of proton pump inhibitor in each section is present after at least about 30 minutes of mixing the pharmaceutical formulation with water. The pharmaceutical preparation according to claim 1, wherein   If the suspension is completely divided into three equal sections, at least about 70% of the indicated amount of proton pump inhibitor in each section is present after at least about 1 hour of mixing the pharmaceutical formulation with water. The pharmaceutical preparation according to claim 1, wherein   If the suspension is completely divided into three equal segments, the percent labeled value variation between each segment is less than about 11% after at least about 5 minutes of mixing the pharmaceutical formulation with water The pharmaceutical preparation according to claim 1.   If the suspension is completely divided into three equal segments, after at least about 30 minutes of mixing the pharmaceutical formulation with water, the variation in percent value between each segment is less than about 20% The pharmaceutical preparation according to claim 1. (A) a pharmaceutical formulation comprising at least one acid-labile micronized proton pump inhibitor; and (b) at least one antacid, prepared by a method comprising the following steps: Pharmaceutical formulation:
(A) coating at least a portion of at least one antacid with at least a portion of the micronized proton pump inhibitor to form a first blend; and (b) the first blend. Dry blending with at least one other excipient.   The dosage form consists of powders, tablets, bite-disintegration tablets, chewable tablets, caplets, capsules, effervescent powders, fast disintegrating tablets, or aqueous suspensions produced from powders 28. The pharmaceutical formulation of claim 27, which is selected.   28. A pharmaceutical formulation according to claim 27, wherein the dosage form is a powder for suspension.   The proton pump inhibitor is omeprazole, hydroxyomeprazole, esomeprazole, tenatoprazole, lansoprazole, pantoprazole, rabeprazole, dontoprazole, habeprazole, perprazole, lansoprazole, paliprazole, leminoprazole; or their free base, free acid 28. A substituted bicyclic aryl-imidazole selected from the group consisting of: a salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, or prodrug. Pharmaceutical formulation.   The proton pump inhibitor is omeprazole, or a free base, free acid, salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, or prodrug thereof. 27. Pharmaceutical formulation according to 27.   The proton pump inhibitor is esomeprazole, or their free base, free acid, salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, or prodrug, 28. A pharmaceutical formulation according to claim 27.   The proton pump inhibitor is lansoprazole, or a free base, free acid, salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, or prodrug thereof. 27. Pharmaceutical formulation according to 27.   28. The pharmaceutical formulation of claim 27, wherein the at least one antacid comprises at least one soluble antacid.   28. The pharmaceutical formulation of claim 27, wherein the soluble antacid is sodium bicarbonate.   28. The pharmaceutical formulation of claim 27, wherein the at least one antacid is present in an amount of at least about 5 mEq.   28. The pharmaceutical formulation of claim 27, comprising about 500 mg to about 3000 mg of antacid.   One or more excipients selected from the group consisting of mural cell activators, organic solvents, erosion enhancers, diffusion enhancers, antioxidants, and binders, disintegrants, fillers, surfactants, 28. The pharmaceutical formulation of claim 27, further comprising a carrier material selected from the group consisting of solubilizers, stabilizers, lubricants, wetting agents, flocculants, diluents, anti-adhesive agents, and antifoaming agents.   28. A pharmaceutical formulation according to claim 27 comprising at least one flavorant.   28. The pharmaceutical formulation of claim 27, wherein the average particle size of the first blend is from about 10 microns to about 200 microns in diameter.   28. The pharmaceutical formulation of claim 27, wherein at least about 80% of the proton pump inhibitor particles are less than about 40 [mu] m.   A method of treating an acid-related gastrointestinal disorder in a subject in need of treatment by administration of the pharmaceutical formulation of claim 1.   28. A method of treating an acid-related gastrointestinal disorder in a subject in need of treatment by administration of a pharmaceutical formulation according to claim 27.

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